| A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | AA | AB | AC | AD | AE | AF | AG | AH | AI | AJ | AK | AL | AM | AN | AO | AP | AQ | AR | AS | AT | AU | AV | ||
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1 | © 2022 Norn Group | Found a mistake or an omission? Have a suggestion for future improvement? Share your feedback here. | |||||||||||||||||||||||||||||||||||||||||||||||
2 | Disease/definitions | Aging | Clinical | Animal models | Miscellaneous | ||||||||||||||||||||||||||||||||||||||||||||
3 | Organ | Indication | Sub-indication(s) | Preclinical (animal) assays | Human diagnostic measurements | Etiological hypothesis and acceptance | References used for columns D-F | Incidence at age 25 (M/F) | Incidence at age 50 (M/F) | Incidence at age 75 (M/F) | References used for columns H-J | Aging biology strongly implicated | Aging biology weakly implicated | References used for columns L+M | Patient population (US, 2022 unless noted) | References for column S | Prognosis | Current Standard of Care Treatments | Clinical endpoints | References for columns Q-S | Total trial duration (months)* | Trial enrollment (# people): Q1, Q2, Q3 | |||||||||||||||||||||||||||
4 | Phase 1 | Phase 2 | Phase 3 | Phase 1 | Phase 2 | Phase 3 | |||||||||||||||||||||||||||||||||||||||||||
5 | Q1 | Q2 | Q3 | Q1 | Q2 | Q3 | Q1 | Q2 | Q3 | Q1 | Q2 | Q3 | Q1 | Q2 | Q3 | Q1 | Q2 | Q3 | Current Clinical Pipeline (link) | How well do mice model? | Species that spontaneously get disease | Species with human-like anatomy + physiology | Notes on model access/logistics | References for columns AN-AQ | Existing political lobbying strength for this disease | Existing umbrella organization political lobbying strength | Disease costs/market (US) | References for AU | |||||||||||||||||||||
6 | Brain | Alzheimer's | Familial AD (early onset), late onset AD, mixed dementia | Neuropsychological testing; imaging (PET, CT, MRI, multiphoton); biomarkers in CSF and blood; histology | Plaque formation; cognitive function; behavioral function | Dominant hypothesis (amyloid beta) strongly supported by human genetics but recently under attack due to failure of treatments - i) accumulation of amyloid β (Aβ) plaques (ii) accumulation of hypophosphorylated tau protein in the form of intracellular neurofibrillary tangles (NFT) (iii) sustained inflammation and (iv) cerebrovascular damage and dysfunction | https://www.nature.com/articles/s41572-021-00269-y ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785514/ | Minimal | <<1000 | ~4000 | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943081/ See also: https://www.nature.com/articles/ncomms11398; https://doi.org/10.1111/jgs.16027 | Impaired autophagy, inflammation, protein aggregation, vascular aging | AGE accumulation, cellular senescence, epigenetic changes, ER stress, immunosenescence (reduced clearance of pathogens), metabolic dysfunction, mitochondrial dysfunction | https://doi.org/10.1016/S1474-4422(15)70016-5 ; https://www.jci.org/articles/view/158453 ; https://pubmed.ncbi.nlm.nih.gov/30530798 ; https://doi.org/10.1111/febs.14332 ; https://pubmed.ncbi.nlm.nih.gov/30936558/ ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355252/ ; https://www.nature.com/articles/s41419-022-05153-5 | 5.8 million (2020, out of 329.5 million Americans) | CDC | 7.6 years (but dependent on age at diagnosis) | No interventions to treat underlying disease. Cholinergic agents used to improve impaired cognitive function but don't halt progress of disease. | Cognitive and functional measures, MRI imaging | https://doi.org/10.1016/S2666-7568(21)00140-9 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061129/; https://alzres.biomedcentral.com/articles/10.1186/s13195-014-0087-9; | 6 | 14 | 33 | 20 | 32 | 45 | 22 | 35 | 50 | 16 | 36 | 53 | 39 | 72 | 168 | 205 | 421 | 933 | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9066743/ | 2 | Grey mouse lemurs recapitulate some features | Nonhuman primates (esp. macaques), dogs | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253109/pdf/nihms839392.pdf; https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/trc2.12114 | 3 | 1 (brain) | $305 billion | https://aaic.alz.org/downloads2020/2020_Facts_and_Figures_Fact_Sheet.pdf | ||
7 | Brain | Vascular dementia | Small vessel dementia, hypoperfusion dementia, multi-infarct dementia, hereditary vascular dementia, mixed dementia | Cerebral blood flow assays (e.g. laser speckle flowmetry); neuropsychological testing; imaging (PET, CT, MRI, multiphoton); histology | Cognitive function; blood-based biomarkers; imaging | Strokes (recurrent or acute), hemorrhages, loss of BBB permeability, general breakdown of the cerebrovascular system - etiology is unclear | https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC2685259 ; https://doi.org/10.1016/S0140-6736(15)00463-8 ; https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3058404/ | Minimal | No data | No data | https://www.alz.org/alzheimers-dementia/facts-figures | Inflammation, vascular aging (arterial stiffness, microvascular rarefaction, narrowing of blood vessels) | Cellular senescence, ER stress, impaired autophagy, mitochondrial dysfunction, oxidative stress | https://doi.org/10.1016/j.arr.2016.09.007 ; https://doi.org/10.1002/jcp.27332 ; https://www.hindawi.com/journals/omcl/2015/504678/ | 1.9 million | https://www.hindawi.com/journals/bmri/2014/908915/ | 6.5 years (but dependent on age at diagnosis) | None | Cognitive and functional measures | https://doi.org/10.1016/S2666-7568(21)00140-9 ; https://www.ahajournals.org/doi/10.1161/jaha.117.005568 | 12 | 20 | 46 | 22 | 37 | 46 | 25 | 40 | 52 | 18 | 40 | 80 | 51 | 95 | 215 | 210 | 349 | 543 | https://www.ahajournals.org/doi/full/10.1161/JAHA.117.005568 | 1.5 | Dogs recapitulate some features | Dogs, nonhuman primates | https://doi.org/10.1186/s12916-017-0793-9 (see Table 1 for breakdown of specific animal models) | Although less prevalent than AD, VaD costs more per patient | https://doi.org/10.1016/S0022-510X(02)00257-5; https://www.ahajournals.org/doi/10.1161/01.STR.0000017878.85274.44 | ||||
8 | Brain | Parkinson's | Idiopathic, early-onset, familial | Behavioral and motor tests (e.g. locomotor activibity, gait analysis, grip strength), imaging (e.g. dopamine transporter levels) | Medical history; neurological examination; CSF and blood biomarkers (e.g. alpha-synuclein species); imaging (e.g. dopamine transporter levels); responsiveness to levo-DOPA | Degeneration of dopaminergic neurons in the midbrain that are part of the basal ganglia—>not enough dopamine; degeneration of noradrenergic neurons; presence of Lewy bodies. Molecular mechanisms of pathogenesis largely unknown. Certain genetic mutations/variants and environmental risk factors are associated with susceptibility to PD, however this is a multifactorial disease so studies altering only one factor typically do not replicate the etiology of PD. | https://link.springer.com/article/10.1007/s10654-011-9581-6 ; https://www.ncbi.nlm.nih.gov/books/NBK536725/ | Minimal | 6.2 (M), 5.1 (F) | 140.7 (M), 78.4 (F) | https://www.researchgate.net/publication/10734381_Incidence_of_Parkinson's_Disease_Variation_by_Age_Gender_and_RaceEthnicity (note: 2003, small sample size. For age 50, averaged stats for 40-49 and 50-59) | ER stress, impaired autophagy, inflammation, mitochondrial dysfunction, protein aggregation | AGE accumulation, cellular senescence, oxidative stress, telomere attrition | https://doi.org/10.1016/j.freeradbiomed.2017.10.379 ; https://movementdisorders.onlinelibrary.wiley.com/doi/pdf/10.1002/mds.27037 ; https://www.sciencedirect.com/science/article/pii/S0753332221001128 ; https://doi.org/10.1016/j.tins.2014.02.010 ; https://doi.org/10.1111/ene.12252 ; https://doi.org/10.1002/mds.21867 ; https://www.sciencedirect.com/science/article/pii/S0753332221001128 ; https://www.frontiersin.org/articles/10.3389/fnins.2019.00560/full ; https://doi.org/10.1155/2013/239854 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698446/ ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355252/ | 0.9 million (2020) | Parkinson's Foundation | PD is a progressive neurodegenerative disorder in which patients can do well for a number of years with dopamine-related drugs to boost or replace dopamine. Dopamine drugs do little to alleviate non-motor symptoms, which may appear before motor symptoms, and include constipation, disrupted sleep, and depression. | No interventions to alter underlying degenerative process; treatment centered on reducing effect of distressing symptoms e.g. levodopa to increase dopamine levels, deep brain stimulation, along with non-drug therapies like exercise | Functional scores (UPDRS, Hoehn and Yahr); self-administered questionnaire; wearables e.g. Parkinson’s Kinetigraph; balance tests | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142835/ | 4 | 10 | 18 | 14 | 24 | 39 | 20 | 27 | 37 | 15 | 24 | 50 | 22 | 42 | 77 | 103 | 249 | 419 | https://content.iospress.com/download/journal-of-parkinsons-disease/jpd219006?id=journal-of-parkinsons-disease%2Fjpd219006; https://www.nature.com/articles/nrd.2018.136 | 1.5 | None known (possibly because of shorter lifespan of most other species) | Nonhuman primates e.g. macaques | https://www.hindawi.com/journals/pd/2011/658083/; https://febs.onlinelibrary.wiley.com/doi/full/10.1111/j.1742-4658.2012.08491.x; https://onlinelibrary.wiley.com/doi/pdf/10.1002/bies.10067?casa_token=0-wZWMg0m48AAAAA:5oWeHL_2u9jMxQokdpO0bPMZMyMAsYtbnJZU24gRXT9ZbLcTmN_Jo-prHs3FVINYRCkKlrGy7n_XWkNR | 2 | $25.4 billion | https://www.nature.com/articles/s41531-020-0117-1 | |||
9 | Brain | Frontotemporal dementia | Neuropsychological testing; imaging (PET, CT, MRI, multiphoton); biomarkers in CSF and blood; histology | Differential diagnosis via behavioral change progression; family history and genetic testing; neuropsychological testing; bloodwork; imaging (MRI, FDG-PET, CT) | Sporadic or genetic. Possibly: TAR DNA-binding protein; mutations in progranulin gene, C9orf72, and other less common genes | https://www.sciencedirect.com/science/article/pii/S0140673615004614?casa_token=yjteX4uRpPQAAAAA:oUiNj5jtFVAogdB4LzUIgFXFgc5GOrcLCU-gdfDbqO8vETNBmvZI0UK424BP2pU5hrn7zwF0glXK; https://www.sciencedirect.com/science/article/pii/S1474442210702994?casa_token=3IUZ8NP1wucAAAAA:WjjKlDhOWFITefhwknUMqj0zqSmla2633_wTurTZ6LOtkf4XhwOm6BeSJQqUHMtYfymFxAqSX9fS; https://www.science.org/doi/full/10.1126/science.1134108?casa_token=b0QBXUwWSS0AAAAA%3AUnb6NCgFvrOzTw_szrqSQUHUgeRo8zs6VN6BJ6lXZTglmnKunxO7HtzMiN8zPwGguRfO4IhrYvG07TQT; https://www.nature.com/articles/nature05016; https://www.nature.com/articles/nature05017; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892118/#R14 | Minimal | 1.34 | 14.95 | https://alzres.biomedcentral.com/articles/10.1186/s13195-020-00753-9/tables/1 ; see also https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983262/ | Inflammation, impaired autophagy, mitochondrial dysfunction, protein aggregation | https://www.nature.com/articles/s41582-019-0231-z ; https://doi.org/10.1093/brain/awu138 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243049/ | 1.5 million | https://www.mayoclinic.org/diseases-conditions/frontotemporal-dementia/symptoms-causes/syc-20354737 | 7.6 years (but dependent on age at diagnosis) | No interventions to treat the actual disease; treatment centered on reducing effect of distressing symptoms e.g. SSRIs and antipsychotics to aid mood and reduce psychosis, aggressive behavior, agitation | Functional measures; neuropsychological scores; cortical volume; white matter integrity | https://doi.org/10.1016/S2666-7568(21)00140-9 ; https://www.sciencedirect.com/science/article/pii/S0140673615004614?casa_token=yjteX4uRpPQAAAAA:oUiNj5jtFVAogdB4LzUIgFXFgc5GOrcLCU-gdfDbqO8vETNBmvZI0UK424BP2pU5hrn7zwF0glXK; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038533/; https://www.aafp.org/afp/2010/1201/p1372.html; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351779/ | 21 | 36 | 59 | 31 | 44 | 69 | 34 | 43 | 64 | 12 | 16 | 34 | 18 | 34 | 52 | 43 | 73 | 203 | https://www.nature.com/articles/s41582-020-0330-x | 1.5 | None known | Nonhuman primates | https://www.nature.com/articles/s41593-018-0236-8 | 1 | Similar to VaD, FTD is less prevalent than AD but more expensive per patient | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711509/ | |||||
10 | Brain | Stroke | Ischemic | Histology; MRI; functional and neurological measures (e.g. Bederson score) | Imaging (CT, MRI); laser Doppler flowmetry; bloodwork; angiography; ECG; functional analysis | Blood clot in cerebral artery -> ischemic cascade (increased oxidative stress, mitochondrial disfunction, induction of inflammatory processes) -> infarction | https://doi.org/10.1111/j.1747-4949.2008.00187.x; https://doi.org/10.1016/S0006-8993(01)03270-X ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229752/ | < 31 (M), 26 (F) | < 201 (M), 142 (F) | 546 (M), 482 (F) | https://www.ahajournals.org/doi/10.1161/STROKEAHA.120.028910 | Inflammation, vascular aging | Cellular senescence, oxidative stress | https://www.nature.com/articles/nrneurol.2016.125 ; https://www.nature.com/articles/s41380-021-01361-1 | 0.7 million / year | CDC | >5 years | Intravenous thrombolysis (for patients presenting up to 4.5 hours after symptom onset); mechanical thrombectomy/clot extraction (for patients selected by imaging presenting up 24 hours after symptom onset). Secondary preventation after ischemic stroke: Single or dual antiplatelet therapy (aspirin + P2Y12 inhibitor); Anticoagulants; HMG-CoA reductase inhibitors (statins); blood pressure control; lifestyle modification (treatments depend on results of evaluation and specific risk factors present) | Functional measures (e.g. modified Rankin scale, Barthel index, National Institute of Health Stroke Scale) | https://doi.org/10.1016/S1474-4422(20)30101-0; https://doi.org/10.1161/STROKEAHA.118.022913 | 14 | 39 | 52 | 16 | 31 | 48 | 26 | 52 | 69 | 23 | 35 | 59 | 18 | 49 | 110 | 165 | 656 | 5,135 | https://doi.org/10.1080/13543784.2022.2072725 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276937/ | 2.5 | Rats e.g. spontaneously hypertensive stroke-prone rat (SHRSP), dogs | Nonhuman primates (to lesser degree: pigs, dogs, sheep, rats) | Rats often preferred to mice because they are easier to image | https://doi.org/10.1016/j.brainresbull.2016.02.016; https://www.understandinganimalresearch.org.uk/news/10-years-of-rat-research-how-stroke-studies-have-evolved; https://www.ahajournals.org/doi/full/10.1161/STROKEAHA.117.017112 | N/A | 4 (heart and stroke) | $169.6 billion | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105541/ | |
11 | Brain | Stroke | Hemorrhagic | Rupture of blood vessel -> hematoma, increase in intracranial pressure -> secondary injury caused by inflammation, disruption of BBB, ROS | https://www.mayoclinic.org/diseases-conditions/stroke/diagnosis-treatment/drc-20350119; https://bestpractice.bmj.com/topics/en-us/1079; https://www.ncbi.nlm.nih.gov/books/NBK559173/ | 0.1 million / year | CDC | 1 month | None routine; surgical evacuation for minority with infratentorial hemorrhage, oral nimodipine for sub-arachnoid hemorrhage | 33 | 36 | 45 | 16 | 30 | 38 | 43 | 49 | 86 | 12 | 30 | 56 | 20 | 40 | 68 | 91 | 360 | 610 | ICH: https://www.sciencedirect.com/science/article/pii/S2352396422000640 ; https://link.springer.com/article/10.1007/s12975-020-00830-z ; https://doi.org/10.1016/j.ebiom.2019.06.012 ; https://link.springer.com/article/10.1007/s11910-021-01144-9 ; SAH: https://www.ahajournals.org/doi/full/10.1161/STROKEAHA.119.025997 | $66.1 billion | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105541/ | |||||||||||||||||||
12 | Heart | Heart failure | Reduced ejection fraction (systolic) | Histology; echocardiography; MRI; hemodynamics | Electrocardiography; blood oxygen level; hemodynamics (bloodflow eg stroke volume) | Reduced ability to pump blood, linked to cardiomyocyte death and loss of force/pumping (cell-cell coordinated coupling involved) and fibrosis | Consulting | Minimal | 140 | 2000 (M), 1400 (F) | https://academic.oup.com/eurheartj/article/25/18/1614/400157#89260333 (2004, incidence at 50-59, 75-79 respectively) | ECM stiffening, vascular aging | Impaired autophagy, inflammation, metabolic dysfunction, mitochondria dysfunction, oxidative stress | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588179/ ; https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.117.311082 ; https://www.nature.com/articles/s41569-019-0315-x | 6.2 million (2020) | CDC | <4 years | Multiple drugs: angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), beta‐blockers, angiotensin receptor‐neprilysin inhibitor (ARNI), mineralocorticoid receptor antagonist (MRA), digitalis, diuretics, hydralazines, nitrates, SGLT-2 inhibitors, CRT, hemodynamically guided management. For later stages, implanted devices like defibrillators. End stage: heart transplant. | Ultimate endpoint: Reduction in mortality or rehospitalization | https://doi.org/10.1016/j.jacc.2017.08.074; https://www.acc.org/latest-in-cardiology/journal-scans/2017/11/10/22/18/heart-failure-with-preserved-borderline-aha-2017 | 3 | 11 | 29 | 14 | 21 | 34 | 27 | 40 | 60 | 18 | 40 | 48 | 23 | 56 | 129 | 223 | 713 | 3,588 | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348963/; https://doi.org/10.1080/13543784.2019.1551357 | 2.5 | None known | Pigs, dogs (more secondary blood vessel formation than humans), mice, cats | Large animal models are ~$10k | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452204/ | N/A | $30.7 billion | https://www.ajmc.com/view/heart-failure-population-health-considerations | ||
13 | Heart | Heart failure | Preserved ejection fraction (diastolic) | Reduced intake of blood caused by myocyte hypertrophy and stiffness, fibrosis reduce heart function. | Consulting | MRA (spironolactone), sacubitril/valsartan, SGLT-2 inhibitors, hemodynamically guided management. | Ultimate endpoint: Reduction in mortality or rehospitalization | ||||||||||||||||||||||||||||||||||||||||||
14 | Cardiovascular | Atherosclerosis | Histology; morphology (esp. size of atherosclerotic lesion); imaging (MRI) | Blood lipid profile (LDL cholesterol); blood pressure; medical history (risk factors e.g. smoking) | Chronic inflammation due to lipid retention->development of lesions/plaques that break down, causing blood clot to form and occlude the arterial lumen | https://www.ncbi.nlm.nih.gov/books/NBK507799/ ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785239/ ; https://www.nature.com/articles/s41586-021-03392-8 | <1000 | 7000 | 33000 (M), 30500 (F) | *South Korea, https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-019-7439-0/figures/2 | Cellular senescence, immunosenescence, inflammation, mitochondrial dysfunction | ER stress, oxidative stress, telomere attrition | https://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.111.261388 ; https://academic.oup.com/cardiovascres/article/79/3/360/610497 ; https://www.nature.com/articles/s41569-020-0431-7 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785239/ ; https://doi.org/10.1161/CIRCRESAHA.110.224766 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112585/ | 4.6 million | https://www.omicsonline.org/united-states/atherosclerosis-peer-reviewed-pdf-ppt-articles/#:~:text=The%20Statistics%20for%20the%20extrapolated,4.6%20million%20people%20in%20USA. | Moderately improved if risk factors (e.g. high blood pressure, LDL cholesterol) managed; bad if atherosclerosis results in condition like heart failure. Anti-inflammatory therapies recently shown to have some benefit and under further evaluation. | Coronary angioplasty, coronary artery bypass surgery, statins to lower LDL cholesterol and increase HDL cholesterol, anticoagulants, antiplatelet medicines, blood pressure medicines, diabetes medicines | Increased blood flow in arteries | https://www.cell.com/fulltext/S0092-8674(01)00238-0, https://www.ncbi.nlm.nih.gov/books/NBK507799/ | 16 | 30 | 38 | 18 | 30 | 52 | 22 | 43 | 64 | 21 | 86 | 107 | 32 | 82 | 149 | 152 | 580 | 7,106 | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901406/ | 2.5 | Monkeys and pigs when fed high fat, high cholesterol diets | Nonhuman primates, dogs, pigs | https://academic.oup.com/cardiovascres/article/79/3/360/610497, https://www.frontiersin.org/articles/10.3389/fcvm.2019.00046/full#B5, https://www.frontiersin.org/articles/10.3389/fcvm.2019.00046/full#B5, Li et al. 2011, https://www.cell.com/fulltext/S0092-8674(01)00238-0 | 1 | $330 billion* | https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000558?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org#d3e119149 | ||||
15 | Liver | Non-alcoholic steatohepatitis | Patients (loosely) separated by fibrosis stage, F1-4 | Mainly histological assessment of fibrosis, steatosis, and immune infiltration. ALT/AST levels in blood, transcriptomics also used | Imaging (esp. MR elastography); ALT/AST blood levels; liver biopsy; non-invasive tests (NITs) | Hepatocyte death, with accumulation of toxic lipids and ER stress likely involved, leading to (mutually reinforcing) immune infiltration and stellate cells converting to fibrotic myofibroblasts. Well accepted as core framework, details being discussed. Clearly some genetic modifiers of disease risk. Dietary factors (glucose, fructose, saturated fatty acids) are important contributors. | https://www.nature.com/articles/s41591-018-0104-9 | <150 | 400 | 480 | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866219/ | ER stress, inflammation, metabolic dysfunction (insulin resistance, hyperlipidemia) | Cellular senescence | https://www.nature.com/articles/s41591-018-0104-9 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930975/ | 17 million (2015) | Hepatology | Highly variable; order of 1/3 patients regress spontaneously, progressors usually decades to progress to cirrhosis and/or hepatocellular carcinoma. Elevated risk of cardiovascular events is strongest risk factor in NASH. | Lifestyle modifications. End-stage: liver transplantation | Phase 3: NAS and Fibrosis scoring systems for biopsy histology. Earlier/secondary measurements include non-invasive liver stiffness and adipocity, blood cholesterol, ALT/AST levels, sometimes inflammatory cytokines . | https://doi.org/10.1002/hep.24376 | 6 | 10 | 20 | 15 | 25 | 35 | 42 | 52 | 55 | 24 | 42 | 75 | 40 | 76 | 139 | 143 | 178 | 212 | Lots of candidates, but prominent failures in past few years. Most are focused on metabolism, some on fibrosis or inflammation. An FXR agonist came closest to approval, and is still a focus. Interestingly, most therapeutic failures are anti-inflammatory drugs (e.g., targeting ASK-1, CCR2/5, PDE4, caspases). Inflammation seemed like a good target but it may be that if we don't address the metabolic drivers, treating the consequences of lipotoxic injury to hepatocytes is not enough to stop and reverse disease. Reviews: https://www.nature.com/articles/s41575-020-00408-y ; https://www.tandfonline.com/doi/full/10.1080/13543784.2020.1721169 ; https://doi.org/10.1080/13543784.2020.1668926 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9062842/ | 2.5 | Some do when on 'Western diet' (high fat, high sugar, high cholesterol). Female mice are very resistant to diet-induced NASH so most studies are in male mice. | Primates are favored by pharma (although some discount animal models entirely) | Many CROs exist for these models | https://www.sciencedirect.com/science/article/pii/S1521691811000308 | N/A | 1 (liver) | $103 billion | https://doi.org/10.1016/j.jhepr.2020.100142 | |
16 | Liver | Cirrhosis | Compensated | End stage of liver fibrosis caused by excessive immune response to chronic liver disease. Liver injury triggers transdifferentiation of hepatic stellate cells to myofibroblasts, which produce excess deposition of ECM characterizing fibrosis. | https://www.sciencedirect.com/science/article/pii/S149938721830095X#fig0002; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583179/ | ECM imbalance, inflammation | Cellular senescence, mitochondrial dysfunction, oxidative stress | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736713/ ; https://www.jci.org/articles/view/30542 | 0.6 million (2015) | Journal of Clinical Gastroenterology | 9-12 years | Lifestyle modifications; treatment of symptoms e.g. non-selective beta-blockers to treat portal hypertension, diuretics for ascites and edema, lactulose and rifaximin for hepatic encephalopathy | Phase 3: survival; Phase 2: CTP or MELD score, biomarkers e.g. inflammatory cytokines, oxidized albumin, NGAL | https://my.clevelandclinic.org/health/diseases/15572-cirrhosis-of-the-liver; https://www.fda.gov/media/127738/download | 5 | 15 | 31 | 19 | 25 | 35 | 14 | 19 | 28 | 9 | 10 | 18 | 26 | 60 | 155 | 100 | 160 | 306 | 2 | Nonhuman primates | $7.4 billion | https://journals.lww.com/ctg/Fulltext/2019/07000/Increasing_Economic_Burden_in_Hospitalized.12.aspx | |||||||||||||
17 | Liver | Cirrhosis | Non-compensated | 2 years | As above; end stage: liver transplant | https://doi.org/10.1016/j.jhep.2020.08.009 | |||||||||||||||||||||||||||||||||||||||||||
18 | Liver | Hepatocellular carcinoma | Histology; imaging (CT, MRI, ultrasound, PET, optical) | Serum AFP; imaging (esp. CT, MRI); occasionally biopsy | [most frequently] Hepatitis, chronic liver disease, alcohol abuse, non-alcoholic fatty liver disease etc->cirrhosis->metabolic and oxidative injury->cyclical inflammation, necrosis, and repeated compensatory regeneration->genetic errors/mutations, telomere erosion, telomerase reactivation, chromosomal gains, activation of protooncogenes | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063561/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490340/ ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2023919/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4145097/ | Minimal | 17.3 (M), 4.9 (F) | 65.2 (M), 30.3 (F) | SEER Incidence Rates by Age at Diagnosis (2015-2019, incidence at 25-29, 50-54, 75-79 respectively) | DNA damage, inflammation | ECM imbalance (excessive production) | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490340/ | 0.04 million annual cases (2020) | Journal of Clinical Oncology | <1 years for patients with advanced disease; longer in earlier stages | Surgical resection, liver transplantation, transarterial chemoembolization, transarterial radiation, ethanol injection, percutaneous local ablation, microwave ablation, combination immunotherapy regimens (atezolizumab+bevacizumab or durvalumab+tremelimumab or nivolumab+ipilimumab) or tyrosine kinase inhibitors (lenvatinib, sorafenib, cabozantinib, ramucirumab) or anti-VEGF therapies (ramucirumab) | Overall survival; time to recurrence; time to progression / progression-free survival; objective response rate | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063561/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989948/; https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.27443 | 32 | 50 | 67 | 34 | 51 | 77 | 53 | 64 | 86 | 19 | 27 | 66 | 17 | 33 | 65 | 376 | 533 | 702 | https://www.nature.com/articles/nrd.2018.146; https://jeccr.biomedcentral.com/articles/10.1186/s13046-021-01968-w | 3.5 | Possibly mice, woodchuck models for HBV cirrhosis | Nonhuman primates | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800979/; https://www.nature.com/articles/labinvest2012155; https://onlinelibrary.wiley.com/doi/full/10.1111/j.1600-0684.2003.00048.x?casa_token=l3PmH6PquGkAAAAA%3AaeuJdEEvnhdSbq9pQ_AwHZlZm52daHuOjUh-RTyn1V7sKFy3EIG8eDlnsCAnn_qWno9CjlHAGP3pd6IX | 1 | $406 million | https://doi.org/10.1016/j.jhep.2008.07.029 | ||||
19 | Lung | Idiopathic pulmonary fibrosis | Fibrosis (histology, enzymatic); lung function; immune infiltration; alveolar structure | Spirometry; imaging (X-ray, CT); pulse oximetry and arterial blood gas analysis; bronchoscopy; lung biopsy | Epithelial cell death -> inflammation and fibrosis, well supported but not completely understood | (know from experience) | Minimal | 6.2 (M), 5.4 (F) | 38.5 (M), 19.5 (F) | https://www.atsjournals.org/doi/pdf/10.1164/rccm.200602-163OC (narrow case definition, incidence at 18-34, 45-54, 75+ respectively) | Cellular senescence, impaired cell replacement, inflammation, telomere attrition | DNA damage, ER stress, mitochondrial dysfunction, | https://www.nature.com/articles/ncomms14532 ; https://www.sciencedirect.com/science/article/abs/pii/S2213260020303647 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775527/ ; https://pubmed.ncbi.nlm.nih.gov/29567124/ | 0.1 million | https://medlineplus.gov/genetics/condition/idiopathic-pulmonary-fibrosis/#:~:text=Idiopathic%20pulmonary%20fibrosis%20has%20an,sporadic%20form%20of%20the%20disease. | 3-4 years | Nintedanib, pirfenidone both improve QoL but not prognosis | Forced vital capacity; 6-min walk test; hospitalization; mortality | https://doi.org/10.1513/AnnalsATS.201706-423ED ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162322/ | 18 | 26 | 30 | 22 | 36 | 50 | 26 | 32 | 46 | 8 | 15 | 29 | 35 | 64 | 174 | 128 | 274 | 515 | https://www.nature.com/articles/nrd.2017.170; https://doi.org/10.1016/j.resinv.2020.04.002 | 2 | Dogs, cats, donkeys get fibrosis | Ferrets, larger animals | (know from experience) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532376/; https://doi.org/10.1165/rcmb.2017-0096ST; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824038/ | 1 | 2 (lung) | >$3 billion | https://www.ajmc.com/view/improving-outcomes-managing-costs-idiopathic-pulmonary-fibrosis | |||
20 | Lung | Chronic obstructive pulmonary fibrosis | Fibrosis (histology, enzymatic); imaging (e.g. CT); lung function; immune infiltration; alveolar structure | Spirometry (and other pulmonary function tests); imaging (X-ray, CT); pulse oximetry and arterial blood gas analysis | Chronic inflammation usually triggered by inhaled noxious gases (smoking in 85-90% of cases), which increase lung oxidative stress. There is also an excess ratio of proteases to antiproteases, leading to small airway fibrosis, lung parenchymal destruction (emphysema) and mucus hypersecretion (chronic bronchitis). Rare patients have genetic Alpha-1 deficiency which involves lack of antiproteases. | https://www.lung.org/lung-health-diseases/lung-disease-lookup/copd/what-causes-copd#:~:text=It%20increases%20your%20risk%20of,men%20who%20have%20never%20smoked. | Minimal | 800 (M), 300 (F) | 1700 (M), 600 (F) | *Netherlands https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005388/ | Cellular senescence, inflammation, oxidative stress, telomere attrition | Impaired autophagy | https://pubmed.ncbi.nlm.nih.gov/33811810/, https://www.sciencedirect.com/science/article/pii/S135730391200031X?casa_token=WJJFyDWy4PAAAAAA:HjozMPX0ra7JiPPAi5qmtTg7vvLt-HZqVrZjPpkskHaCrbo91aG-AixfIlEA6CENefiYTgvqHgvq | 16.4 million (2018) | https://www.lung.org/research/trends-in-lung-disease/copd-trends-brief/copd-prevalence | 5 years, reduces to 2 years for severe COPD | Inhaled long-acting bronchodilators, inhaled corticosteroids in selected patients, pulmonary rehab, supplemental oxygen, surgery | Forced expiratory volume (FEV1); functional questionnaires (usually SGRQ); transition dyspnea index (TDI); time to first / frequency of / number of COPD exacerbation(s); mortality | https://www.emedicinehealth.com/ask_life_expectancy_for_copd/article_em.htm; https://doi.org/10.3389/fphar.2019.01519 | 3 | 5 | 10 | 6 | 9 | 18 | 10 | 15 | 22 | 24 | 32 | 55 | 48 | 97 | 281 | 227 | 607 | 1,055 | https://www.nature.com/articles/nrd4254; https://doi.org/10.1002/cpt.1540; https://www.tandfonline.com/doi/abs/10.1080/13543784.2020.1769064 | 2 | None known | None known | Mice show pathophysiology but not structurally same as humans. | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2494776/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414171/; https://www.karger.com/Article/FullText/502489 | 1 | $30 billion | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694800/ | |||
21 | Systemic | Type 2 diabetes | Blood glucose concentration, gulcose and insulin tolerance, histology (pancreas, liver, muscle), transcriptomics | Blood glucose concentration (average levels measured by glycated hemoglobin (A1C) test, random or fasting blood sugar tests also used); urine tests (presence of glucose?); serum insulin or c-peptide levels; occasionally imaging (ultrasound, MRI) | Caused by two main factors: insulin resistance (IR) and defective insulin secretion by pancreatic beta-cells. IR -> increased blood sugar levels -> more insulin production in pancreas (hyperinsulinemia) and amyloid deposition + genetic susceptibility -> deficient insulin secretion from beta-cells -> hyperglycemia | https://doi.org/10.3390/ijms21176275; https://doi.org/10.2337/dc12-1805; https://www.sciencedirect.com/science/article/pii/B9780128113530000439 | 320 | 1010 | 580 | https://www.cdc.gov/diabetes/data/statistics-report/newly-diagnosed-diabetes.html | AGE accumulation, deregulated nutrient sensing (hyperactivation of mTOR), metabolic dysfunction (insulin resistance), inflammation | Cellular senescence, ER stress, mitochondrial dysfunction, oxidative stress, protein aggregation (amylin) | https://www.hindawi.com/journals/omcl/2016/1810327/ ; https://link.springer.com/article/10.1007/s11010-014-2236-7 ; https://www.science.org/doi/10.1126/science.1104343 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492843/ ; https://doi.org/10.1016/j.mad.2018.03.010 ; https://doi.org/10.1210/endocr/bqab136 ; https://doi.org/10.3389/fendo.2021.650158 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477358/ ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903318/ | 34 million (2019) | CDC | Age dependent. ~7 years for those diagnosed at 75. | Diet and exercise to maintain target blood sugar level; usually metformin, often acarbose (outside US), possibly DPP-4 inhibitors, GLP-1 receptor agonists, or SGLT-2 inhibitors, occasionally sulfonylureas, glinides, thiazolidinediones; possibly insulin therapy; possibly bariatric surgery | HbA1c (change from baseline); time to hyperglycemia rescue; fasting plasma glucose, insulin, c-peptide (change from baseline); body weight; postprandial blood glucose profile | https://www.mayoclinic.org/diseases-conditions/type-2-diabetes/diagnosis-treatment/drc-20351199, clinicaltrials.gov | 3 | 5 | 10 | 9 | 13 | 20 | 16 | 22 | 31 | 24 | 33 | 54 | 59 | 150 | 291 | 285 | 492 | 822 | https://doi.org/10.1080/17460441.2020.1791078 | 2.5 | Cats, some pig strains, nonhuman primates | Nonhuman primates (e.g. high fructose-fed rhesus monkeys), pigs, dogs | https://www.sciencedirect.com/science/article/pii/B9780128113530000439; https://doi.org/10.1093/ilar.47.3.186; https://diabetesjournals.org/diabetes/article/65/9/2700/40154/Pancreatic-Cells-From-Mice-Offset-Age-Associated | 2 | 2 | $237 billion | https://www.diabetes.org/about-us/statistics/cost-diabetes | |||
22 | Bone/joint | Osteoporosis | Post-menopausal (type 1), senile (type 2) | Bone mineral density test via dual-energy x-ray absorptiometry (DXA) and micro-CT; bone turnover biomarkers for formation (e.g. serum osteocalcin and P1NP), resorption (e.g. C-terminal telopeptides) and osteoclast number (e.g. TRACP); histology (static and dynamic histomorphometry) | Bone mineral density test via DXA; Physical exam to check for height/weight loss, posture changes, balance and gait, muscle strength (can you stand from sitting without using your arms?); Quantitative ultrasound of the heel to test for bone loss (after which, DXA if necessary); Fracture Risk Assessment Tool (FRAX) | Imbalance between bone resorption and formation rates: increased rate of bone turnover possibly due to shortening of osteoblast lifespan and elevation or maintenance of osteoclast activity | https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00010-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1934590921000102%3Fshowall%3Dtrue; https://www.bones.nih.gov/health-info/bone/osteoporosis/overview; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534332/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5335887/; https://www.sciencedirect.com/science/article/pii/S0025619611622143?casa_token=hBK10mgD0n8AAAAA:qCRm4o2qierQXZrIzvcFgHeU6H13M8HlKPrO-EYQ2QC0Qd1ykEsdKL4TA-j8VAK18CSlvxl5vNeW; https://www.sciencedirect.com/science/article/pii/S1530891X20412121?casa_token=GZ6MuL5nR60AAAAA:e-AnD3B2re7lngT1DlBvTf1JApYe7BiOe17RnBIBiJ4VGnNwABtZiRYVokj-MMionDmTGJP4mWMQ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768298/ ; https://doi.org/10.1080/13547500601070842 | No data | 2,247 (M), 2,313 (F) | 4,718 (M), 6,616 (F) | https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.2072 - see also: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244291 | Cellular senescence, DNA damage, impaired cell replacement, metabolic dysfunction, mitochondrial dysfunction | Impaired autophagy, telomere attrition | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037620/ ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816306/ ; https://www.nature.com/articles/nm.4385 ; https://pubmed.ncbi.nlm.nih.gov/32669663/ | 10 million (2010) | https://health.gov/healthypeople/about/workgroups/osteoporosis-workgroup#:~:text=In%20the%20United%20States%2C%20an,at%20increased%20risk%20for%20osteoporosis. | Age dependent. Men treated at age 55 years or younger or women treated at age 70 years or younger have an average 15 years life expectancy. | Pharmacological: Bisphosphonates (e.g. Alendronate, Risendronate) or Denosumab injections; Exercise; Good nutrition; Teriparatide (PTH 1-34), Evenity (monoclonal antibody against Sclerostin) | Bone mass and bone strength | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768298/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5335887/ ; https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.2478 | 5 | 8 | 10 | 22 | 38 | 76 | 22 | 37 | 60 | 26 | 45 | 198 | 46 | 103 | 239 | 135 | 332 | 833 | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798872/ | 2 | None known | Nonhuman primates, pigs, sheep (to a degree), dogs (to a degree) | https://link.springer.com/article/10.1007/s00586-008-0813-8; https://link.springer.com/article/10.1007/s00586-008-0813-8; https://asbmr.onlinelibrary.wiley.com/doi/full/10.1359/jbmr.080516 | 1 | N/A | $22 billion | https://link.springer.com/article/10.1007/s00198-010-1419-7 | ||
23 | Bone/joint | Osteoarthritis | Histology; structural imaging (CT, MRI, ultrasound); molecular imaging (PET, optical); omics (esp. transcriptomics, proteomics); pain/functional outcomes/biomechanics (e.g. gait, muscle strength, weight bearing, joint stiffness, joint strength) | Physical examination; arthroscopy; synovial fluid sampling; imaging e.g. MRI, radiographs with Kellgren-Lawrence radiographic grading scheme | Interplay between systemic (advanced age, female gender, certain ethnicities, genetics, developmental conditions) and local factors (obesity, knee injury, knee laxity) causing degradation of cartilatge, theckning of bone and some degree of inflammation in the joint lining. | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920533; https://www.aafp.org/afp/2012/0101/p49.html ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327515/ ; https://onlinelibrary.wiley.com/doi/full/10.1002/jor.23343 ; https://journals.sagepub.com/doi/full/10.1177/1947603511402665 | Minimal | 5,000 (M), 10,500 (F) | 17,500 (M), 26,000 (F) | https://doi.org/10.1016/j.joca.2020.03.004 | AGE accumulation, ECM imbalance (low synthesis, high degradation), inflammation | Cellular senescence, mitochondrial dysfunction, oxidative stress | https://doi.org/10.1016/S0140-6736(11)60243-2 ; https://pubmed.ncbi.nlm.nih.gov/33208917/ ; https://www.jci.org/articles/view/95147 ; https://www.nature.com/articles/nm.4324 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525396/ | 32.5 million (2014) | OA Action | Depends on which joints are affected, and to what degree—some patients are unaffected, others experience severe disability. | Non-pharmacological: exercise, weight loss, braces, cranes, insoles; Pharmacological: Paracetamol/acetaminophen, NSAIDs, hyaluronic acid injections, glucocorticoid injections; Surgical: joint replacement surgery | Pain and disability reduction | https://www.ncbi.nlm.nih.gov/books/NBK482326/; https://www.aafp.org/afp/2012/0101/p49.html | 6 | 14 | 26 | 10 | 15 | 21 | 12 | 16 | 23 | 17 | 34 | 57 | 50 | 122 | 291 | 235 | 376 | 606 | https://doi.org/10.1016/j.bcp.2019.02.034 | 3 | Many including mice, guinea pigs, dogs, sheep, goats, cows, horses | Horse, nonhuman primates; no single "gold standard" model | https://www.sciencedirect.com/science/article/pii/S1063458416304782; https://www.sciencedirect.com/science/article/pii/S1063458412000544; https://www.sciencedirect.com/science/article/pii/S1063458406003244; https://journals.sagepub.com/doi/full/10.1177/0300985815588611 | 1 | 2 (arthritis) | $16.5 billion | https://www.cdc.gov/arthritis/data_statistics/cost.htm | |||
24 | Bone/joint | Rheumatoid arthritis | Seropositive (positive for Rheumatoid Factor) or Seronegative | Histology; radiographic imaging; blood tests (CRP level, RF and anti-CCP antibodies); urinary excretion rates of joint destruction biomarkers (HP and LP) | Radiographic imaging; blood tests (ESR, CRP level, RF and anti-CCP antibodies) | Genetic susceptibility (including human leukocyte antigen (HLA) alleles), epigenetic modifications (e.g. DNA methylation at EXOSC1), and environmental risk factors (e.g. smoking, bacteria, EBV infection) trigger (in a manner incompletely understood) the citrullination of antigens -> activation of antigen presenting cells (APCs), migration to lymph nodes -> formation of autoantibodies (ACPAs and RF), migration to joint tissue -> inflammation of synovial membrane (synovitis), angiogenesis and pannus -> cartilage and bone destruction, joint damage. RA is 2-3x more prevalent among females, perhaps due to immune stimulating effects of estrogen. | https://journals.sagepub.com/doi/full/10.1177/0300985815588612; https://www.frontiersin.org/articles/10.3389/fimmu.2022.887460/full; https://pubmed.ncbi.nlm.nih.gov/11001374/ ; https://pubmed.ncbi.nlm.nih.gov/28451788/ ; https://www.nature.com/articles/nrdp20181 | 4.0 (M), 12.6 (F) | 28 (M), 66 (F) | 81 (M), 122 (F) | https://academic.oup.com/rheumatology/article/56/5/736/2864858 | Immunosenescence, inflammation | Cellular senescence, telomere attrition | https://pubmed.ncbi.nlm.nih.gov/26212057/ ; www.ncbi.nlm.nih.gov/pmc/articles/PMC263838/ | 1.5 million (2007) | Arthritis Foundation | Age dependent. Average 26.3 years life expectancy after diagnosis. | Depends of length of RA history: NSAIDs, steroids, csDMARDs, tsDMARDs (JAKi), biological agents | Pain and improved physical function; decreased global assessment of disease activity | https://www.mayoclinic.org/diseases-conditions/rheumatoid-arthritis/diagnosis-treatment/drc-20353653; https://onlinelibrary.wiley.com/doi/10.1002/art.41597 | 6 | 15 | 27 | 14 | 20 | 26 | 22 | 32 | 49 | 19 | 32 | 63 | 70 | 152 | 274 | 127 | 359 | 637 | https://link.springer.com/article/10.1007/s00281-017-0623-3 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500842/ ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179789/ | 2 | None known | Nonhuman primates, pigs (immune system more closely aligned than NHPs) | https://www.frontiersin.org/articles/10.3389/fimmu.2019.00203/full or https://www.karger.com/Article/FullText/508239#ref124 or https://www.nature.com/articles/ncprheum0973 or https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1789807/ or https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02402-z ; | 1 | $19.3 billion | https://pubmed.ncbi.nlm.nih.gov/19908947/ | |||
25 | Reproduction | Menopause | Hormone levels (esp. FSH, estrogen, progesterone); histology; cognitive (e.g. Moris water maze tests) | Usually diagnosed by presentation of symptoms (e.g. vasomotor, irregular periods); FSH and estradiol levels | Ovarian dysfunction and hypothalamic-pituitary-ovarian feedback loop desensitization to estrogen leading to decrease in follicle number and insensitivity of remaining follicles to estrogen which triggers ovulation. Also hypothesis that aging of the central control of ovulation in the hypothalamus might have a role. | https://www.mayoclinic.org/diseases-conditions/menopause/symptoms-causes/syc-20353397 ; https://www.nice.org.uk/guidance/ng23/chapter/Recommendations#diagnosis-of-perimenopause-and-menopause ; https://journals.lww.com/grh/Fulltext/2018/06000/The_etiology_of_menopause___not_just_ovarian.1.aspx | Minimal | Average age at menopause is 51 | Minimal | https://my.clevelandclinic.org/health/diseases/21138-premature-and-early-menopause#:~:text=Premature%20menopause%20happens%20to%20about,in%20about%205%25%20of%20women. | AGE accumulation, cellular senescence, DNA damage, epigenetic changes, ER stress, inflammation, mitochondrial dysfunction, oxidative stress, telomere attrition | https://academic.oup.com/humupd/article/28/2/172/6464146 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995944/ ; https://doi.org/10.1093/humrep/det383 ; https://pubmed.ncbi.nlm.nih.gov/26629734/ ; https://pubmed.ncbi.nlm.nih.gov/27562289 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3952404/ | 50 million (2020) | North American Menopause Society | Highly variable, but age dependent. Those with early menopause live 3.5 years longer than those with late menopause. | Hormone replacement therapy (including tibolone, estrogen +/- progestin/SERM); for vaginal symptoms: vaginal estrogen / DHEA / oral ospemiphene testosterone for postmenopausal HSDD | Symptomatic relief; prevention of osteoporosis | https://www.mayoclinic.org/diseases-conditions/menopause/diagnosis-treatment/drc-20353401 ; https://www.clinicaladvisor.com/home/topics/ob-gyn-information-center/early-menopause-associated-with-shorter-life-expectancy-early-diagnosis-of-type-2-diabetes/ | 2 | 4 | 13 | 18 | 31 | 50 | 16 | 23 | 37 | 23 | 33 | 56 | 60 | 104 | 249 | 257 | 514 | 780 | Mainly dietary supplements and behavioural intervention, few compounds in trials https://www.clinicaltrials.gov/ct2/results?cond=menopause&term=&cntry=&state=&city=&dist= | 1 | Whales i.e Killer | Rhesus macaque | No other species gets menopause other than 4 species of whale. Rhesus macaque maintain cycles till death but pattern does change. | https://www.science.org/content/article/study-suggests-surprising-reason-killer-whales-go-through-menopause OR https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2553520/#:~:text=Reproductive%20senescence%20has%20been%20more,age%20%5B38%2C%2039%5D | 1 | N/A | >$100 million | https://womensmentalhealth.org/posts/the-immense-burden-of-menopausal-symptoms/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620512/ | |||
26 | Eye | Age-related macular degeneration | "Wet AMD" | Histology; imaging (e.g. fundus photography, optical coherence tomography (OCT), electron microscopy); omics (esp. transcriptomics, proteomics); Miles assay of vascular permeability | Age-Related Eye Disease Study (AREDS) classification; retinal imaging (e.g. fundus fluorescein angiography, fundus autofluorescence imaging, near-infrared reflectance, optical coherence tomography) | Interference with Vascular Endothelial Growth Factor (VEGF) function-->cessation of vascular growth, neovascular regression, dysregulation of the complement system | https://www.sciencedirect.com/science/article/pii/S0140673612602827?casa_token=Q2FARXQvV64AAAAA:2wQ6j89eOByoFhFw67u8ZnwMM7dKRf3QS-nZ8S1yN73d4BnPQxbwKgzlZSq6bg4G0N04pRt6gTay; https://pubmed.ncbi.nlm.nih.gov/35122134/; https://www.nejm.org/doi/full/10.1056/NEJMoa054481; https://journals.sagepub.com/doi/abs/10.1177/1120672119857896 | Minimal | 20 (M), 10 (F) 490 (M), 320 (F) | 490 (M), 320 (F) | https://www.sciencedirect.com/science/article/pii/S0002939415001919 | Cellular senescence, DNA damage, inflammation | Mitochondrial dysfunction | https://www.sciencedirect.com/science/article/pii/S0140673612602827?casa_token=Q2FARXQvV64AAAAA:2wQ6j89eOByoFhFw67u8ZnwMM7dKRf3QS-nZ8S1yN73d4BnPQxbwKgzlZSq6bg4G0N04pRt6gTay; https://journals.lww.com/internat-ophthalmology/Citation/2021/06140/Gene_Therapy_in_the_Treatment_of_Geographic.19.aspx; https://iovs.arvojournals.org/article.aspx?articleid=2164895 | 11 million (2020) | https://www.brightfocus.org/sources-macular-degeneration-facts-figures | Poor; disease is chronic and progressive, leads to more severe vision loss than dry AMD | Laser photocoagulation (rarely used), photodynamic therapy (rarely used), VEGF inhibitors, visual rehabilitation | Visual gains, visual stabilisation, improved reading ability and mobility | https://www.sciencedirect.com/science/article/pii/S0140673612602827?casa_token=Q2FARXQvV64AAAAA:2wQ6j89eOByoFhFw67u8ZnwMM7dKRf3QS-nZ8S1yN73d4BnPQxbwKgzlZSq6bg4G0N04pRt6gTay; https://www.sciencedirect.com/science/article/pii/S0161642007002333?casa_token=Eo8rqx3HVRQAAAAA:QyLxxKBT0Yg-8a52kJxX42g5bpuz39_Lv3EjHYThVjCH6iCk9HIkx; https://www.nejm.org/doi/full/10.1056/NEJMoa054481 DbX7bh2PWr7AakyPNEkK-UB | 14 | 18 | 33 | 16 | 27 | 37 | 27 | 34 | 48 | 13 | 40 | 50 | 30 | 86 | 156 | 241 | 382 | 674 | https://doi.org/10.1016/j.drudis.2022.04.013; https://doi.org/10.1111/bph.15459 | 3 | Cynomolgus monkeys | "Nonhuman primates are the only animals with a retinal structure closely resembling that found in humans, most notably the presence of a macula". Pig eyes are the closest to humans of the nonhuman primates. No single animal model develops all the signs of AMD in a progressive manner. Several are good for certain facets of the disease: Simian primates (drusen development); mice (changes in Bruch membrane, inflammation; retinal pigment epithelium and photoreceptor loss) | https://www.sciencedirect.com/science/article/pii/S0002944010644276?casa_token=juH5857x8OEAAAAA:FoylCq2gME4Xrm5ebpic4o6SGtuz09sWoHRtU1U79QifukEJ2paUxqXNEUk4lS1sowvWJ_wpoyL0; https://www.sciencedirect.com/science/article/pii/S004269890700329X; https://iovs.arvojournals.org/article.aspx?articleid=2164895; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186726/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186726/; https://www.sciencedirect.com/science/article/pii/S0098299712000635?casa_token=UxuTRi4pNMYAAAAA:oB5N0fD12__MvfhN-r7VYWzRze4vIiR6paYJB7EVWQR5b_O2AW3DCiCLrfZxb2pdeSCXf4s5SEQ3; https://www.nature.com/articles/nm950; https://www.sciencedirect.com/science/article/pii/S0024320521007980?casa_token=wPIjv8zfhXAAAAAA:MtBwms-qcspa-SpwOp6t6g9W2Sr69d37qdCjNUXVb9UPv6irXxvxxmfAzT0zdfzTLXSRYpB23NIE | 1 | 2 (eye diseases) | $600 million | https://www.brightfocus.org/macular/article/age-related-macular-facts-figures | ||
27 | Eye | Age-related macular degeneration | "Dry AMD" | Unclear, but possibly intrinsic and extrinsic stressors of the poorly regenerative retinal pigment epithelium, e.g. oxidative stress caused by the high metabolic demand of photoreceptors, photo-oxidation, and environmental stressors such as cigarette smoke. Certain genetic mutations, dysregulation of the complement system, mitochondrial dysfunction, inflammation are also associated with dry AMD. | https://www.sciencedirect.com/science/article/pii/S0140673612602827?casa_token=Q2FARXQvV64AAAAA:2wQ6j89eOByoFhFw67u8ZnwMM7dKRf3QS-nZ8S1yN73d4BnPQxbwKgzlZSq6bg4G0N04pRt6gTay; https://pubmed.ncbi.nlm.nih.gov/24433969/; Richard et al. 2021; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424580/; https://www.aaojournal.org/article/S0161-6420(13)00942-1/fulltext | Poor; disease is chronic and progressive; half of patients develop dry AMD in both eyes within 7 years of initial diagnosis | None as yet; some evidence for dietary interventions for slowing disease progression | Change in geographic atrophy area, visual gains, visual stabilisation, improved reading ability and mobility | https://www.sciencedirect.com/science/article/pii/S0140673612602827?casa_token=Q2FARXQvV64AAAAA:2wQ6j89eOByoFhFw67u8ZnwMM7dKRf3QS-nZ8S1yN73d4BnPQxbwKgzlZSq6bg4G0N04pRt6gTay; https://www.sciencedirect.com/science/article/pii/S016164201932353X; https://pubmed.ncbi.nlm.nih.gov/24433969/; Arabi and Shahraki 2021; Richard et al. 2021; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424580/; https://www.aaojournal.org/article/S0161-6420(13)00942-1/fulltext; https://www.aaojournal.org/article/S0161-6420(17)30968-5/fulltext; https://www.nature.com/articles/s41467-018-04175-y | https://www.sciencedirect.com/science/article/pii/S0002944010644276?casa_token=juH5857x8OEAAAAA:FoylCq2gME4Xrm5ebpic4o6SGtuz09sWoHRtU1U79QifukEJ2paUxqXNEUk4lS1sowvWJ_wpoyL0; https://www.sciencedirect.com/science/article/pii/S004269890700329X; https://iovs.arvojournals.org/article.aspx?articleid=2164895; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186726/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186726/; https://www.sciencedirect.com/science/article/pii/S0098299712000635?casa_token=UxuTRi4pNMYAAAAA:oB5N0fD12__MvfhN-r7VYWzRze4vIiR6paYJB7EVWQR5b_O2AW3DCiCLrfZxb2pdeSCXf4s5SEQ3; https://www.nature.com/articles/nm950; https://www.sciencedirect.com/science/article/pii/S0024320521007980?casa_token=wPIjv8zfhXAAAAAA:MtBwms-qcspa-SpwOp6t6g9W2Sr69d37qdCjNUXVb9UPv6irXxvxxmfAzT0zdfzTLXSRYpB23NIE | |||||||||||||||||||||||||||||||||||||||
28 | Eye | Glaucoma | Primary open-angle, primary closed-angle | Intraocular pressure measurement (tonometry), ocular blood flow | Tonometry, visual field test, pachymetry, gonioscopy, imaging esp. optical coherence tomography (OCT) | Primary open-angle glaucoma: intraocular pressure-induced stress and strain->mechanical axonal damage and disruption of axonal transport->interrupted retrograde delivery of essential trophic factors to retinal ganglion cells->degeneration of retinal ganglion cells->higher intraocular pressure; other factors, including blood flow and ischemia may have role. Primary closed-angle glaucoma: [most commonly] resistance to aqueous humor flow->acqueous humor accumulates behind iris->iris convexity increases->angle closure | https://www.nature.com/articles/nrdp201667; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523637/, https://www.sciencedirect.com/science/article/pii/S0039625707001889?casa_token=JIvjTDOelGMAAAAA:uWOlBPjJQthtZUBfKdDEArnC_rUHXxrxDg61-TL6QUL8fr4YUA6kCT0w2WWEfr9KIy6fW7Dy4pxS , https://www.sciencedirect.com/science/article/pii/S1350946220301051 | Minimal | 110 | 370 | https://iovs.arvojournals.org/article.aspx?articleid=2161444 | DNA damage, mitochondrial dyfunction, oxidative stress | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2526097/ ; https://doi.org/10.1016/j.survophthal.2007.08.011 ; https://doi.org/10.1016/j.exer.2010.07.015 | 3 million (2004) | Glaucoma Research Foundation | Primary open-angle glaucoma: Vision loss is permanent, actual blindness is uncommon, majority of patients maintain useful vision through their lifetime, but a significant proportion loses vision resulting in driving ineligibility or partial sight certification; Primary closed-angle glaucoma: blindness is more common | Prostaglandin analogues, beta-blockers, diuretics, cholinergic agonists, alpha agonists, rho kinase inhibitors, argon laser trabeculoplasty, selective laser trabeculoplasty, micropulse laser trabeculoplasty, laser peripheral iridotomy, laser iridoplasty, trabeculectomy, glaucoma drainage implants, nonpenetrating glaucoma surgery, microinvasive glaucoma surgery, incisional glaucoma surgery | Lower intraocular pressure | https://www.sciencedirect.com/science/article, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523637, https://www.nature.com/articles/6702284 | 4 | 5 | 14 | 5 | 9 | 17 | 12 | 17 | 27 | 24 | 30 | 55 | 46 | 102 | 171 | 190 | 420 | 643 | https://doi.org/10.1080/14728214.2022.2110240 | 2 | Some rodents, monkeys | Nonhuman primates | https://www.sciencedirect.com/science/article/pii/S001448350800434X?casa_token=yqdkrISwCCsAAAAA:WSqf_TwU_ZHHQSsayW827AzWy0GRHyVhbErHRtf6bQwtNqKhTXLYat1iCl0IIkwP_o6jpLJmGzSz#bib36, John 2005; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364028/ | 1 | $2.9 billion | https://pubmed.ncbi.nlm.nih.gov/17159036/ | ||||
29 | Eye | Diabetic retinopathy | Non-proliferative, proliferative | Histology (e.g. trypsin digest), omics (e.g. genomics, transcriptomics, proteomics), ocular blood flow, retinal inflammation biomarkers (e.g. TNF-alpha and ICAM-1), electrophysiological testing, imaging (fundus photography (FP), fundus fluorescein angiography (FFA) and optical coherence tomography (OCT)) | FP; FFA; OCT; OCT-Angiography | Hyperglycemia due to diabetes induces microangiopathy in the retina, which results in increased vascular permeability of blood-retinal barrier and leakage. Accumulation of fluid in the macula due to breakdown of the blood-retinal barrier can cause vision loss (diabetic macular edema). Apoptosis of pericytes and endothelial cells results in capillary occlusion and retinal ischemia, increasing VEGF levels which promote neovascularization. | https://journals.biologists.com/dmm/article/5/4/444/3291/Update-on-animal-models-of-diabetic-retinopathy; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518557/pdf/jciinsight-2-93751.pdf; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380708/ | 17,460 (M), 12, 070 (F) * | 26,160 (M), 10,810 (F) | 13,690 (M), 5,850 (F) | *Taiwan, 2011 (ages 20-39, 40-59, 60-79 respectively) doi:10.1001/jamaophthalmol.2014.859 | Inflammation, metabolic dysfunction, oxidative stress | AGE accumulation, mitochondrial dysfunction | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289197/pdf/cia-16-1367.pdf ; https://journals.biologists.com/dmm/article/5/4/444/3291/Update-on-animal-models-of-diabetic-retinopathy ; https://doi.org/10.1371/journal.pone.0139664 ; https://www.mdpi.com/2079-7737/8/2/31/htm ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951818; | 4.1 million (2004) | JAMA Opthamology | Depends on stage. For review of prognostic models, see: https://www.nature.com/articles/s41433-018-0322-x | Laser photocoagulation; surgical vitrectomy; intraocular injections of steroids and VEGF inhibitors, combined VEGF and Ang2 inhibitors, steroid implants (Iliuvien, and Ozurdex) | Visual acuity, diabetic retinopathy severity score (DRSS), OCT central macular thickness, OCT biomarkers such as DRIL | https://www.nature.com/articles/s41433-018-0322-x; https://journals.biologists.com/dmm/article/5/4/444/3291/Update-on-animal-models-of-diabetic-retinopathy | 13 | 32 | 57 | 30 | 33 | 47 | 28 | 41 | 75 | 7 | 25 | 33 | 20 | 36 | 86 | 270 | 466 | 819 | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061411/ | 3 | Pigs, dogs | Pigs, dogs, nonhuman primates, zebrafish (cheaper but less similar, hyperglycemia is induced) | https://link.springer.com/article/10.1007/s11892-017-0913-0; https://jbiomedsci.biomedcentral.com/articles/10.1186/1423-0127-20-38; https://journals.biologists.com/dmm/article/5/4/444/3291/Update-on-animal-models-of-diabetic-retinopathy; https://www.hindawi.com/journals/jdr/2013/106594/ | 1 | $500 million | https://pubmed.ncbi.nlm.nih.gov/17159036/ | |||
30 | Skin/hair | Alopecia (hair loss) | Androgenetic | Duration of hair cycles (e.g. via contrast-enhanced phototrichogram); area of hair regrowth; hair weight, density, length, shaft diameter | Scalp examination; trichoscopy; standardized scalp global photography | AGA stems from a combination of genetic and hormonal factors. Male AGA is a substantially (~80%) hereditary trait with polygenic origin. Dihydrotestosterone (DHT), which is metabolized from testosterone by 5-alpha reductase, has a high affinity for the androgen receptor (AR). DHT is thought to produce follicle miniaturization, but how this occurs and why it is opposite to the effect of androgens on hair follicles in other areas e.g. beard, axillary, pubic hair is unsettled. Variation of the AR gene (which resides on the X chromosome) accounts for about 40% of AGA heritability. | https://doi.org/10.1002/der2.58; https://www.ncbi.nlm.nih.gov/books/NBK278957/; https://journals.lww.com/jewds/Fulltext/2013/09000/Androgenetic_alopecia__update_on_epidemiology,.1.aspx; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174066/ | No data | No data | No data | https://pubmed.ncbi.nlm.nih.gov/9865198/ | Impaired cell replacement | DNA damage, inflammation, oxidative stress | https://www.ncbi.nlm.nih.gov/books/NBK278957/ ; https://doi.org/10.1002/der2.58 ; https://doi.org/10.1111/j.1468-3083.2008.02937.x | 80 million | https://medlineplus.gov/genetics/condition/androgenetic-alopecia/#frequency | No significant effect on life expectancy | Topical minoxidil; 5-alpha reductase inhibitors (e.g. finasteride); occasionally low level laser therapy, hair transplant surgery | Hair count, hair growth, hair fiber diameter | https://www.uspharmacist.com/article/treatment-options-for-androgenetic-alopecia ; https://journals.lww.com/jewds/Fulltext/2013/09000/Androgenetic_alopecia__update_on_epidemiology,.1.aspx | 4 | 9 | 12 | 12 | 17 | 20 | 12 | 16 | 21 | 20 | 32 | 42 | 33 | 48 | 95 | 115 | 161 | 353 | Oral minoxidil, anti-prolactin monoclonal antibody injection, topical prostaglandin. See: https://doi.org/10.1080/13543784.2019.1568989 | 1.5 | Bears, lions, nonhuman primates | Nonhuman primates esp. stump-tailed macaque | https://onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2230.2002.01086.x; https://onlinelibrary.wiley.com/doi/full/10.1002/ski2.15 | 1 | N/A | Estimate not found | https://www.aafp.org/pubs/afp/issues/1999/0415/p2189.html | ||
31 | Bladder cancer | Bladder cancer | Non-muscle invasive (NMIBC), muscle invasive (MIBC) | Histology; imaging (CT, MRI, ultrasound, optical); gene expression; bladder weight measurement | Cystoscopy; bladder sonography; urine cytopathology; transurethral resection; imaging (X-ray, CT, MRI, ultrasound) | Genetic and epigenetic changes around tumor suppressor genes and oncogenes of unclear origin, exacerbated by carcinogens. Papillary tumors characterized by activating mutations in FGFR2, non-papillary bladder cancer involves inactivation of tumor suppressors including TP53 and RB1. | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957872/; https://www.oncotarget.com/article/17714/text/ | Minimal | 11.9 | 131.3 | https://gis.cdc.gov/Cancer/USCS/#/Demographics/ (2018, male female combined, incidence at 25-29, 50-54, 75-79 respectively) | DNA damage, epigenetic changes (hypermethylation of tumor suppressors) | Inflammation | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957872/ ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696263/ ; https://pubmed.ncbi.nlm.nih.gov/24818724/ | 0.7 million (2019) | NCI | 77% 5 year relative survival rate | Surgery (transurethral resection of bladder tumor, cystectomy); intravesical therapy (immunotherapy with BCG or chemotherapy); radiation; systemic chemotherapy; IV infusions of immune checkpoint (PD-1 and PD-L1) inhibitors; FGFR inhibitors e.g. erdafitinib | Response rate and duration; event free survival (time to recurrence, progression); urine markers? | https://www.cancer.org/cancer/bladder-cancer/treating.html ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321095/ ; https://www.fda.gov/media/101468/download ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832566/pdf/blc-1-2-blc150016.pdf ; clinicaltrials.gov | 32 | 51 | 71 | 43 | 62 | 87 | 43 | 47 | 58 | 17 | 26 | 124 | 21 | 40 | 58 | 304 | 542 | 802 | https://www.nature.com/articles/nrd.2016.141; https://doi.org/10.1080/14712598.2022.2082869 | 2.5 | Some rat strains (e.g. Brown Norway and DA/Han), dogs | Dogs | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593682/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036476/ | 1 | 4 (all cancers) | $9.4 billion | https://progressreport.cancer.gov/after/economic_burden | ||
32 | Breast cancer | Breast cancer | Luminal A, luminal B, luminal B-like, HER-2 enriched, triple negative | Histology; imaging (PET, MRI, high frequency ultrasound, optical); omics (esp. DNA methylation, genomics, transcriptomics); hormone levels; apoptosis assays (e.g. TUNEL) | Local breast biopsy (occasionally also fine needle aspiration) and bilateral breast imaging using mammography (ie. low dose radiography, ultrasonography, and occasionally digital breast tomosynthesis); MRI and PET scanning may also be used to complement imaging and look for local or distant tumor spread. | The primary risk factors for breast cancer (beyond age) are genetic and hormone (i.e. estrogen) related. Most breast cancers are associated with multiple, low-penetrant genetic mutations and epigenetic alternations inhibiting DNA repair pathways, growth control mechanisms and chromosomal stability, but about 10% of breast cancers are induced by germline inheritance of a highly penetrant loss-of-function mutation in a tumor-suppressing gene such as BRCA1 and BRCA2. Nearly 80% of breast cancers are characterized by their overexpression of steroid hormone receptors (ER, PR) and/or amplification of the human epidermal growth factor receptor-2 (HER2) gene. For 70-80% of breast cancers, estrogen promotes and drives breast cancer growth by binding ER, which is a ligand-activated TF that transcriptionally enhances cell proliferation. Up to 20% of breast cancers have amplified HER2 (also referred to as ERBB2), which encodes a membrane-localized receptor tyrosine kinase that when overexpressed is constitutively activated to drive uncontrolled cell proliferation, cell survival, local invasiveness and distant metastasis. Triple-negative breast cancers (those that do not overexpress ER, PR or HER2) are the most common type of breast cancer associated with inherited BRCA1 related mutations. | https://www.nature.com/articles/s41572-019-0111-2; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681186/ ; https://link.springer.com/article/10.1007/s00432-010-0957-x ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778915/ | 10.3 (F) | 229.8 (F) | 461.1 (F) | https://gis.cdc.gov/Cancer/USCS/#/Demographics/ (2018, incidence at 25-29, 50-54, 75-79 respectively) | DNA damage, epigenetic changes (global hypomethylation, hypermethylation of tumor suppressors) | Inflammation | https://www.nature.com/articles/s41572-019-0111-2 ; https://doi.org/10.3390/cancers13153918 ; https://www.mdpi.com/1422-0067/19/4/1166/htm | 3.7 million (2019) | NCI | 91% 5 year relative survival rate | Surgery, radiation (usually EBRT, sometimes brachytherapy); for estrogen or progesterone-receptor positive cancers: hormone therapy (selective estrogen receptor modulators e.g. tamoxifen, selective estrogen receptor degraders, aromatase inhibitors, ovarian suppression), CDK4/6 inhibitors, mTOR inhibitor, PI3K inhibitor (for those with PIK3CA mutation); HER2 monoclonal antibodies or kinase inhibitors for HER2-positive cancer; PARP inhibitors for those with BRCA mutation; antibody-drug conjugate for triple negative cancers (ER-, PR-, HER2-); immune checkpoint (PD-1) inhibitors. | Event free survival (time to recurrence, progression); overall survival; response rate and duration; percentage change in tumor size | https://www.nature.com/articles/s41572-019-0111-2 ; https://www.cancer.org/cancer/breast-cancer/treatment.html ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237237/ ; https://ascopubs.org/doi/full/10.1200/edbk_280451 | 29 | 44 | 66 | 41 | 57 | 83 | 53 | 80 | 117 | 17 | 33 | 54 | 33 | 60 | 119 | 226 | 488 | 1,006 | https://www.nature.com/articles/d41573-021-00018-6; https://doi.org/10.1016/j.ctrv.2017.11.003 | 2.5 | Cats and dogs frequently develop spontaneous BC; rodents rarely develop spontaneous mammary cancers during their lifespan unless genetically engineered to do so | Cats, dogs, pigs | Transgenic mice for BC research generally are 200-300 USD per subject (Jackson Laboratory), while transgenic pigs (e.g., the Oncopig) can be in the range of 1-2K USD. Per diem, drug and labor costs also ~order of magnitude higher. | https://www.frontiersin.org/articles/10.3389/fonc.2022.788038/full#T2; https://www.sciencedirect.com/science/article/pii/B9780124158948000403 | 2 | $29.8 billion | https://progressreport.cancer.gov/after/economic_burden | ||
33 | Gastrointestinal | Colorectal cancer | CMS1 (immune), CMS2 (canonical), CMS3 (metabolic), CMS4 (mesenchymal) | Histology; imaging (e.g. optical, ultrasound); omics (esp. DNA methylation, genomics, transcriptomics) | Guaiac fecal occult blood or fecal immunochemical tests, sigmoidoscopy, colonoscopy, CT scan | Genetic and epigenetic mutations (including mutations leading to DNA replication errors, oncogene activation and tumor suppressor inactivation) allow colonic epithelium to develop precancerous lesions that can form invasive carcinoma. ~70% of colon cancer is sporadic, while ~30% of patients have family history, of which a third is caused by known inherited syndromes including familial adenomatous polyposis and Lynch syndrome | https://www.nature.com/articles/nm.3967; https://www.ncbi.nlm.nih.gov/books/NBK470380/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795459/pdf/ijms-22-00200.pdf | 3.4 | 62.7 | 169 | https://gis.cdc.gov/Cancer/USCS/#/Demographics/ (2018, male female combined, incidence at 25-29, 50-54, 75-79 respectively) | DNA damage, epigenetic changes (hypermethylation of tumor suppressors, global hypomethylation), inflammation | Mitochondrial dysfunction, telomere attrition | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795459/pdf/ijms-22-00200.pdf ; https://clinicalepigeneticsjournal.biomedcentral.com/track/pdf/10.1186/s13148-019-0801-3.pdf ; https://www.sciencedirect.com/science/article/pii/S0748798319309266#! ; https://www.nature.com/articles/s41577-021-00534-x ; https://doi.org/10.1016/j.dld.2018.02.009 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934464/ | 1.4 million (2019) | NCI | 65% 5 year relative survival rate | Endoscopic or surgical resection; ablation or embolization; radiation therapy; chemotherapy; IV-infused monoclonal antibodies targeting VEGFs (vascular endothelial growth factors) and EGFR (epidermal growth factors receptor); BRAF inhibitors (for those with BRAF mutation); immune checkpoint (PD-1, CTLA-4) inhibitors | Response rate and duration; event free survival (time to recurrence, progression); overall survival; percentage change in tumor size | https://www.cancer.org/cancer/colon-rectal-cancer/treating.html; clinicaltrials.gov | 26 | 34 | 52 | 33 | 50 | 70 | 34 | 52 | 78 | 20 | 32 | 88 | 39 | 69 | 121 | 292 | 587 | 1,067 | https://www.nature.com/articles/nrd.2017.59 ; https://www.nature.com/articles/s41575-019-0126-x | 3 | Mice, dogs, sheep | Dogs, nonhuman primates (e.g. cotton-top tamarin) | https://pubmed.ncbi.nlm.nih.gov/23076650/; https://pubmed.ncbi.nlm.nih.gov/33916402/ | 1 | $24.3 billion | https://progressreport.cancer.gov/after/economic_burden | |||
34 | Reproduction | Endometrial Cancer | POLE mutated, microsatellite instability, copy number low, copy number high | Histology; imaging (e.g. MRI, CT, optical, ultrasound); omics (esp. DNA methylation, genomics, transcriptomics) | Pelvic exam; ultrasound; hysteroscopy; biopsy; dilation and curettage; CA-125 blood level | Molecular basis largely unclear and subtype-dependent, but hormonal imbalance (esp. high proportion of estrogen to progesterone) thought to stimulate endometrial proliferation and hyperplasia -> atypical premalignant lesions -> endometrioid carcinoma with oncogene mutations (CTNNB1, KRAS, and POLE), tumor suppressor mutations (in PTEN) and defects in DNA mismatch repair. | https://www.ncbi.nlm.nih.gov/books/NBK525981/; https://www.mdpi.com/1422-0067/22/17/9274/htm | 2.1 (F) | 48.1 (F) | 91.9 (F) | https://gis.cdc.gov/Cancer/USCS/#/Demographics/ (2018, incidence at 25-29, 50-54, 75-79 respectively) | DNA damage, epigenetic changes (hypermethylation of tumor suppressors) | Inflammation, metabolic dysfunction (insulin resistance), mitochondrial dysfunction, oxidative stress | https://www.nature.com/articles/s41467-021-22560-y ; https://www.tandfonline.com/doi/full/10.4161/epi.5.6.12431 ; https://www.mdpi.com/1422-0067/19/7/2076/htm ; https://www.mdpi.com/2072-6694/12/9/2559/htm ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2966326/ | 0.8 million (2019) | NCI | 81% 5 year relative survival rate | Surgery; radiation (brachytherapy or external beam); for late stage: chemotherapy, hormone therapy (progestins, anti-estrogen drugs like tamoxifen, luteinizing hormone-releasing hormone agonists, aromatase inhibitors), targeted drugs (kinase inhibitors, angiogenesis inhibitors, mTOR inhibitors) | Event free survival (time to recurrence, progression); response rate and duration; overall survival; | https://www.cancer.org/cancer/endometrial-cancer/treating.html; NCI | 43 | 46 | 61 | 43 | 54 | 82 | 70 | 91 | 117 | 24 | 41 | 82 | 29 | 37 | 54 | 117 | 377 | 548 | https://www.nature.com/articles/d41573-022-00016-2; https://www.nature.com/articles/nrd.2017.92 | 2.5 | Rodents (esp Donryu rats) | Nonhuman primates | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121384/pdf/ijms-19-02348.pdf | 1 | $5.8 billion | https://progressreport.cancer.gov/after/economic_burden | |||
35 | Kidney | Kidney Cancer | Renal cell carcinoma (clear cell, papillary, chromophobe, clear cell papillary, collecting duct, medullary), urothelial carcinoma, sarcoma, lymphoma, Wilm's tumor (primarily in children) | Histology; imaging (e.g. optical, MRI); apoptosis assay (e.g. flow cytometry); omics (esp. DNA methylation, genomics, transcriptomics); tumor weight | Imaging (CT scan, MRI, ultrasound); biopsy; urianalysis (blood in urine?) + bloodwork (number of red blood cells) | Unclear, but like other cancers, genetic and epigenetic changes around tumor suppressor genes and oncogenes are implicated e.g. loss of chromosome 3p, inhibition of VHL seen in >90% of cases of clear cell renal cell carcinoma (most common type of kidney cancer) | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850086/pdf/f1000research-7-14298.pdf | 1.3 | 26.1 | 73.1 | https://gis.cdc.gov/Cancer/USCS/#/Demographics/ (2018, male female combined, incidence at 25-29, 50-54, 75-79 respectively) | DNA damage, epigenetic changes (hypermethylation of tumor suppressors) | Deregulated nutrient sensing, telomere attrition, oxidative stress | https://www.nature.com/articles/nrurol.2010.47 ; https://www.nature.com/articles/nrurol.2010.46 ; https://content.iospress.com/articles/kidney-cancer/kca190052#ref001%20ref002 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069705/ ; https://jhoonline.biomedcentral.com/articles/10.1186/s13045-015-0180-y | 0.6 million (2019) | NCI | 77% 5 year relative survival rate | Surgery; ablation; drugs targeting angiogensis (including sunitinib, sorafenib, pazopanib, cabozantinib, lenvatinib, bavcizumab, axitinib, tivozanib, belzutifan) or targeting mTOR protein (including temsirolimus, everolimus); immune checkpoint (PD-1, PD-L1, CTLA-4) inhibitors; occasionally cytokines (IL-1 and interferon-alfa); rarely radiation or chemotherapy | Response rate and duration; event free survival (time to recurrence, progression); overall survival; percentage change in tumor size | https://www.cancer.org/cancer/kidney-cancer/treating.html; NCI; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3176905/pdf/conc-18-s11.pdf | 40 | 66 | 93 | 43 | 61 | 91 | 53 | 72 | 99 | 25 | 48 | 133 | 25 | 53 | 96 | 257 | 541 | 781 | https://doi.org/10.1016/j.ctrv.2018.07.009 | 3 | Rodents | Zebrafish, dogs | https://www.sciencedirect.com/science/article/pii/S1936523319306394#bb0415 | 1 | $9.7 billion | https://progressreport.cancer.gov/after/economic_burden | |||
36 | Blood | Leukemia | Chronic lymphocytic, acute myeloid, chronic myeloid, acute lymphocytic. (Acute = fast onset, associated with less mature hematopoietic precursor cells than chronic.) | Complete blood count; flow cytometry; imaging (optical); omics (e.g. transcriptomics, genomics) | Physical examination (pale skin from anemia, swelling of lymph nodes, and enlargement of liver and spleen); complete blood count (abnormal levels of red or white blood cells or platelets); flow cytometry; peripheral blood smear; bone marrow biopsy; lumbar puncture | Leukemogenesis is subtype dependent, but generally involves somatic mutations, epigenetic modifications and chromosomal alterations that impair control of growth and division of hematopoietic precursor cells (blasts in the case of acute leukemias, or more mature cells in chronic leukemias) -> overcrowding in the bone marrow -> decreased number of red blood cells, platelets and white blood cells -> symptoms such as fatigue, thrombocytopenia, infection | https://www.nature.com/articles/nrc2765.pdf; https://www.sciencedirect.com/science/article/abs/pii/S1521692603000860; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333535/; https://www.nature.com/articles/nrdp201696; https://www.nature.com/articles/nrdp201610 | 2.9 | 11.9 | 66.5 | https://gis.cdc.gov/Cancer/USCS/#/Demographics/ (2018, male female combined, incidence at 25-29, 50-54, 75-79 respectively) | Clonal hematopoiesis, DNA damage, epigenetic changes (hypermethylation of tumor suppressors) | Inflammation | https://doi.org/10.1016/j.molmed.2019.04.006 ; https://doi.org/10.3390/cancers12010103 ; https://doi.org/10.1007/s12185-014-1651-6 ; https://doi.org/10.1158/0008-5472.CAN-06-1681 | 0.5 million (2019) | NCI | 66% 5 year relative survival rate (on average, but highly subtype dependent, better for chronic leukemias) | Chemotherapy; targeted therapy; radiation; stem cell/bone marrow transplant; immunotherapy; CAR-T cell therapy | Response rate and duration; overall survival; event free survival (time to recurrence, progression) | NCI; https://www.mayoclinic.org/diseases-conditions/leukemia/diagnosis-treatment/drc-20374378; https://acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.30622; https://pubmed.ncbi.nlm.nih.gov/29524739/ | 33 | 50 | 75 | 46 | 69 | 96 | 60 | 78 | 110 | 20 | 34 | 64 | 26 | 46 | 84 | 173 | 318 | 539 | AML: https://doi.org/10.3390/cancers12113225 CLL: https://jhoonline.biomedcentral.com/articles/10.1186/s13045-021-01054-w CML: https://www.frontiersin.org/articles/10.3389/fonc.2019.00665/full | 2 | Some rodents e.g. New Zealand black mice spontaneously develop chronic lymphocytic leukemia | Dogs (rarely used), nonhuman primates | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568447/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722578/; https://doi.org/10.3389/fonc.2017.00022 | 3 | $13.6 billion | https://progressreport.cancer.gov/after/economic_burden | |||
37 | Lung | Lung Cancer | Small cell, non-small cell | Histology; imaging (CT, MRI, ultrasound); respiratory function (e.g. via plethysmography); omics (esp. DNA methylation, genomics, transcriptomics); tumor size, body weight, body temperature | Low dose CT; fine needle aspiration or core needle biopsy (often with CT or ultrasound guidance) | Lung cancer can be divided into two main subtypes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which account for 15% and 85% of cases respectively. SCLC is a highly malignant tumor with strong links to tobacco, which causes the dual inactivation of two tumor suppressors, p53 and RB. Conversely, activating oncogenic mutations e.g. in EGFR are often responsible for tumorigenesis in NSCLC (although non-small cells may also have loss of tumor suppressors like p53 and RB). | https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3864624/ ; https://www.nature.com/articles/nrdp20159 ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218036/ | 0.6 | 41.4 | 380 | https://gis.cdc.gov/Cancer/USCS/#/Demographics/ (2018, male female combined, incidence at 25-29, 50-54, 75-79 respectively) | DNA damage, epigenetic changes (hypermethylation of tumor suppressors), oxidative stress | Inflammation | https://www.sciencedirect.com/science/article/pii/S0092867421002907 ; https://doi.org/10.1016/j.freeradbiomed.2013.08.006 | 0.6 million (2019) | NCI | 23% 5 year relative survival rate | Surgery; chemoradiation; immunotherapy; targeted therapy (angiogenesis inhibitors, also KRAS, EGFR, ALK, ROS1, BRAF, RET, MET, NTRK inhibitors) | Overall survival; progression-free survival; objective response rate | NCI; https://www.fda.gov/media/116860/download; https://pubmed.ncbi.nlm.nih.gov/25806152/ | 32 | 44 | 66 | 38 | 53 | 75 | 45 | 69 | 92 | 17 | 38 | 70 | 35 | 62 | 110 | 305 | 503 | 792 | https://www.nature.com/articles/s41392-019-0099-9; https://www.nature.com/articles/d41573-020-00057-5 | 2.5 | Some mice strains, dogs, sheep | Sheep, dogs, nonhuman primates | https://www.hindawi.com/journals/bmri/2015/621324/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2094362/; https://pubmed.ncbi.nlm.nih.gov/25991702/ | 1 | $23.8 billion | https://progressreport.cancer.gov/after/economic_burden | |||
38 | Skin/hair | Melanoma | Superficial spreading, nodular, lentigo, acral lentiginous | Histology; imaging (optical, CT, PET, ultrasound); tumor size, body weight; omics (esp. genomics, transcriptomics, proteomics) | Biopsy (assays include IHC, FISH, CGH, gene expression); imaging (reflectance confocal microscopy, Xray, ultrasound, CT, MRI, PET); blood levels of LDH | Melanoma is characterized by genetic and epigenetic changes around tumor suppressor genes and oncogenes in melanocytes (skin cells producing melanin). Specifically, the majority of sporadic melanomas have activating mutations (e.g. BRAF and RAS genes) that lead to dysregulation of the MAPK pathway and increase cell proliferation. UV radiation exposure is a primary risk factor known to produce DNA strand breaks and ROS. Additionally, with ~10% of patients having family history, melanoma has a hereditary component, including germline mutations in CDKN2A and CDK4. | https://www.cancer.org/cancer/melanoma-skin-cancer/detection-diagnosis-staging/how-diagnosed.html; https://www.nature.com/articles/nrdp20153; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346328/ ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897908/ | 3.9 (M), 7.1(F) | 29.4 (M), 27.3 (F) | 154.2 (M), 55.3 (F) | SEER Incidence Rates by Age at Diagnosis (2015-2019, incidence at 25-29, 50-54, 75-79 respectively) | DNA damage | Immunosenescence, inflammation, oxidative stress | https://www.tandfonline.com/doi/full/10.1586/14737140.2015.961426 ; https://doi.org/10.1016/j.prp.2018.11.020 | 1.4 million (2019) | NCI | 94% 5 year relative survival rate | Surgery; radiation (brachytherapy or external beam); for late stage: immunotherapy (PD-1 inhibitors, PD-L1 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor); targeted therapy (kinase inhibitors, angiogenesis inhibitors, mTOR inhibitors); occasionally chemotherapy, hormone therapy (progestins, anti-estrogen drugs like tamoxifen, luteinizing hormone-releasing hormone agonists, aromatase inhibitors) | Event free survival (time to recurrence, progression); response rate and duration; overall survival; percentage change in tumor size | https://aacrjournals.org/clincancerres/article/18/2/336/77325/New-Challenges-in-Endpoints-for-Drug-Development; https://www.cancer.org/cancer/melanoma-skin-cancer/treating.html; NCI | 33 | 48 | 79 | 42 | 57 | 78 | 41 | 64 | 83 | 22 | 35 | 127 | 23 | 44 | 97 | 235 | 435 | 733 | https://www.nature.com/articles/d41573-022-00075-5 | 2.5 | Sharks, rabbits, horses, penguins, snakes, cows, goats, lions, alpacas, nonhuman primates... | Horses, dogs, pigs, zebrafish, nonhuman primates | https://onlinelibrary.wiley.com/doi/10.1002/path.5505; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832391/pdf/PATH-238-152.pdf; https://www.nature.com/articles/s41684-019-0447-y | 1 | $5.7 billion | https://progressreport.cancer.gov/after/economic_burden | |||
39 | Lymphatic system | Non-Hodgkin Lymphoma | B-cell, T-cell, NK-cell | Histology; imaging (PET, optical); omics (esp. transcriptomics, mutation profiling, proteomics) | Imaging (CT, MRI, ultrasound, PET); biopsy (flow cytometry, immunohistochemistry, chromosome tests, NGS) | Genetic mutations (point mutations or gene rearrangements) in lymphocytes (most commonly B cells, but also T cells) cause uncontrolled division and/or reduce apoptosis. NHL etiology remains poorly understood and varies across subtype, but risk factors include immune-altering conditions like autoimmune disorders (e.g. rheumatoid arthritis), viruses and infections (like HIV/AIDs, H. Pylori infection, EBV, HTLV-1, HCV), immunosuppressant drugs or inherited immune disorders (e.g. Wiskott-Aldrich syndrome), as well as chronic antigen stimulation. The formation of antigen receptors involves gene rearrangements, and errors (like the chromosomal translocations characterizing subtypes such as follicular lymphoma, mantle cell lymphoma and Burkitt lymphoma) can lead to activation of oncogenes. | https://link.springer.com/chapter/10.1007/978-3-319-13150-4_1; https://europepmc.org/article/nbk/nbk559328; https://www.cancer.org/cancer/non-hodgkin-lymphoma/detection-diagnosis-staging/how-diagnosed.html | 3.3 | 20.9 | 98.7 | https://gis.cdc.gov/Cancer/USCS/#/Demographics/ (2018, male female combined, incidence at 25-29, 50-54, 75-79 respectively) | DNA damage | Clonal hematopoesis, immunosenescence, inflammation, | https://immunityageing.biomedcentral.com/track/pdf/10.1186/s12979-018-0130-y.pdf ; https://link.springer.com/article/10.1007/s11912-015-0457-x | 0.8 million (2019) | NCI | 74% 5 year relative survival rate | Radiation therapy; chemotherapy; immunotherapy: monoclonal antibodies targetting B-or T-lymphocyte antigens (CD20, CD19, CD30, CD79b), CAR T-cell therapies; targeted therapy (kinase and BCL2 inhibitors); stem cell transplant | Response rate and duration; Event free survival (time to recurrence, progression); overall survival | https://www.cancer.org/cancer/non-hodgkin-lymphoma/treating.html; NCI | 38 | 62 | 88 | 49 | 79 | 115 | 42 | 80 | 99 | 31 | 51 | 81 | 27 | 46 | 72 | 140 | 305 | 439 | https://www.nature.com/articles/d41573-019-00051-6 | 2 | Dogs, nonhuman primates, genetically-engineered mice | Dogs, nonhuman primates | https://onlinelibrary.wiley.com/doi/10.1002/hon.2017; https://www.frontiersin.org/articles/10.3389/fonc.2017.00022/full; https://www.hindawi.com/journals/ah/2012/701704/ | 1 | $18.6 billion | https://progressreport.cancer.gov/after/economic_burden | |||
40 | Pancreas | Pancreatic Cancer | Exocrine, neuroendocrine | Histology; imaging (ultrasound, MRI, optical); blood biomarkers (e.g. CA19) | Blood biomarkers: CA19-9, CA-50, DUPAN-2, SPAN-1, CEA; imaging: contrast-enhanced multislice CT, MRI, endoluminal ultrasound with fine needle aspiration cytology; laparoscopy with laparoscopic ultrasound | Genetic and epigenetic alternations of oncogenes (esp. K-ras, which is activated in >90% of pancreatic cancers; as well as growth factors and P13K/Akt) and tumor suppressors (inactivation of p53, INK4a/ARF, BRCA2, Smad4); reactivation of developmental signalling (Notch and Hedgehog). Beyond age and race, risk factors include chronic pancreatitis, smoking, high alcohol intake, obesity and pesticides. | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1955499/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319955/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396775/pdf/wjon-10-010.pdf | 0.4 | 12.1 | 81.7 | https://gis.cdc.gov/Cancer/USCS/#/Demographics/ (2018, male female combined, incidence at 25-29, 50-54, 75-79 respectively) | DNA damage, epigenetic changes (hypermethylation of tumor suppressors) | Inflammation | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1955499/ ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319955/ ; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396775/pdf/wjon-10-010.pdf | 0.09 million (2019) | NCI | 5-6 months; 12% 5 year relative survival rate | Surgery; ablation or embolization; radiation; chemotherapy (including gemcitabine with nab-paclitaxel, FOLFIRINOX); EGFR inhibitor; PARP or NTRK inhibitors (for those with BRCA and NTRK mutations respectively); immunotherapy (PD-1 inhibitor) | Objective response rate and duration; event free survival (time to recurrence, progression); overall survival; percentage change in tumor size | NCI; https://www.frontiersin.org/articles/10.3389/fonc.2019.00144/full | 32 | 42 | 67 | 40 | 56 | 81 | 40 | 50 | 72 | 19 | 27 | 36 | 29 | 50 | 95 | 126 | 405 | 587 | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517959/ | 3 | Hamsters | Pigs, dogs | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319955/; https://www.frontiersin.org/articles/10.3389/fonc.2019.00144/full; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995380/; https://www.gastrojournal.org/article/S0016-5085(13)00190-X/fulltext | 2 | $2.7 billion | https://doi.org/10.1016/j.pan.2020.09.002 | |||
41 | Reproduction | Prostate Cancer | Adenocarcinoma (acinar, ductal), transitional cell carcinoma, squamous cell carcinoma, small cell | Histology; blood biomarkers (esp. PSA, genistein); imaging (e.g. optical, MRI); omics (esp. DNA methylation, genomics, transcriptomics); tumor weight and volume | Blood tests (esp. PSA levels); digital rectal examination; imaging (esp. MRI); prostate biopsy | Unclear, but associated with somatic mutations in oncogenes or tumor suppressor genes in the prostate epithelial cell genome, commonly including TMPRSS2–ERG fusion, MYC amplification, PTEN and RB1 deletion and TP53 mutation. Also a hereditary component: approx. 9% of men with prostate cancer have family history, and germline mutations in DNA damage repair such as BRCA1 and BRCA2 are known to increase risk of early onset prostate cancer. | https://www.clinicalkey.com/#!/content/book/3-s2.0-B9780323546423001506; https://www.nature.com/articles/s41572-020-00243-0 | Minimal | 112 (M) | 572 (M) | https://gis.cdc.gov/Cancer/USCS/#/Demographics/ (2018) | DNA damage, epigenetic changes | Mitochondrial dysfunction, inflammation, oxidative stress | https://www.pnas.org/doi/10.1073/pnas.0931396100 ; https://doi.org/10.1016/j.semcancer.2009.02.006 ; https://doi.org/10.1093/carcin/bgy133 ; https://doi.org/10.1016/j.bbcan.2008.11.001 ; https://link.springer.com/chapter/10.1007/978-3-319-95693-0_3 ; https://www.nature.com/articles/pcan201313 | 3.3 million (2019) | NCI | 97% 5 year relative survival rate | Surgery (prostatectomy, orchiectomy); radiation therapy (external beam, brachytherapy, radiopharmaceuticals targeting PSMA or bones); hormone therapy: androgen deprivation therapy (LHRH agonists "medical castration", LHRH antagonists), anti-androgens; PARP-inhibitors for those with BRCA mutation; chemotherapy; occasionally cryotherapy; cancer vaccine (Sipuleucel-T) | Overall survival; metastasis-free survival; PSA levels (change, nadir, time to progression); testosterone (for LHRH agonists) | https://doi.org/10.1016/S0090-4295(02)01585-6; https://journals.lww.com/journalppo/fulltext/2020/01000/surrogate_endpoints_in_localized_prostate_cancer.8.aspx; https://www.cancer.org/cancer/prostate-cancer/treating; NCI | 30 | 39 | 70 | 38 | 56 | 78 | 33 | 61 | 99 | 18 | 37 | 67 | 28 | 47 | 82 | 158 | 392 | 1,091 | https://www.nature.com/articles/d41573-021-00111-w | 2.5 | Some rat strains, dogs | Dogs, nonhuman primates | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644021/; https://www.mdpi.com/2306-7381/1/1/16; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221286/ | 1 | $22.3 billion | https://progressreport.cancer.gov/after/economic_burden | |||
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