医生如何治愈自己的绝症 | Dr. David Fajgenbaum
摘要
宾夕法尼亚大学转化医学教授 Dr. David Fajgenbaum 分享了他的亲身经历：他曾五度濒临死亡，病因是一种名为 Castleman 病的罕见免疫系统疾病。最终，他通过系统性地搜索现有已批准药物，找到了治疗方法。他的经历揭示了医学领域一个巨大的盲区：数千种已批准药物对其原始适应症以外的疾病具有尚未开发的治疗潜力，但目前尚无系统性的努力来识别和推广这些再利用疗法。他现在运营着一家名为 Every Cure 的非营利组织，致力于大规模解决这一问题。
核心要点
- FDA 已批准约 4,000 种药物，对应约 4,000 种疾病，但仍有 14,000 种疾病没有任何获批治疗方案——其中 80% 的药物已成为仿制药，探索新用途毫无经济驱动力。
- 普通小分子药物平均可与体内 20–30 种不同蛋白质结合，这意味着大多数药物实际产生的效果远超其获批适应症。
- 阿司匹林已被证明可降低结肠癌复发风险，尤其对存在 mTOR pathway 突变的患者效果显著，然而这一用途在临床实践中鲜有应用。
- 在乳腺肿瘤周围注射利多卡因，于手术前 8–10 分钟给药，在一项纳入 1,600 名印度患者的试验中显示五年死亡率降低 29%——但这一发现在临床上几乎未获推广。
- 秋水仙碱（传统上用于治疗痛风）已被证实可显著降低曾有心肌梗死病史患者（尤其是合并 diabetes 的患者）的 cardiovascular disease 风险。
- 药物再利用在系统层面遭到忽视，原因在于一旦药物成为仿制药，便没有任何公司有经济动力资助其新适应症的临床试验。
- TNF inhibitors 被发现可阻止患有罕见病 DADA2 的儿童发生卒中——但这一知识的传播历经数年，期间数百名儿童本可获救却不幸离世。
- 患者应积极联系疾病倡导组织，寻找所患疾病领域的全球顶尖专家，并始终追问世界其他地方是否存在替代或超说明书用药方案。
- Sleep deprivation 可能触发危险的细胞因子风暴——小鼠研究显示，睡眠剥夺的小鼠因免疫过度激活而死亡，其中包括 interleukin-6 水平升高，而 interleukin-6 正是 Castleman 病的关键细胞因子。
- Fajgenbaum 的非营利组织 Every Cure 利用人工智能和生物医学知识图谱，系统性地将每种药物与每种疾病进行匹配，目前正在运行九个活跃的药物再利用项目。
详细笔记
核心问题：药物再利用体系的失效
- 目前已有 4,000 种 FDA 批准药物，以及约 18,000 种已知人类疾病。
- 大多数药物影响 40 条以上的生物通路，但获批并被研究的往往只有一两条。
- 一旦药物成为仿制药，所有制药公司的研发便会停止——没有公司愿意为新适应症资助大型临床试验，因为利润太低。
- 结果是：可能挽救生命的治疗方案被束之高阁，患者死于那些”无法治愈”的疾病——而解决方案或许早已静静地摆在某家药店的货架上。
- 制药公司确实会在专利到期前进行药物再利用，但通常是以略微改良剂型的方式在同一疾病领域内操作，而非真正探索全新的适应症。
药物再利用的典型案例
阿司匹林
- 已知用途：止痛、抗血栓、预防心肌梗死。
- 鲜为人知的用途： 降低结肠癌复发风险，尤其对存在 mTOR pathway 突变的患者效果显著。
- 尽管已有发表的证据，这一用途尚未成为标准临床实践。
万艾可（西地那非）/ 希爱力（他达拉非）
- 西地那非最初被开发用于心脏病治疗，后被再利用于 erectile dysfunction（勃起功能障碍）。
- 同时被再利用于儿童肺动脉高压——此前因肺部血流不足而无法正常生活的儿童，如今可以在西地那非的帮助下过上正常生活。
- 他达拉非最初被开发用于前列腺健康与血液循环，后来才被发现可治疗勃起功能障碍。
沙利度胺
- 最初被开发为孕妇止吐药。
- 因其抗血管生成特性（即阻断血管生长）造成了灾难性的先天缺陷（四肢畸形）。
- 同样的作用机制后来被发现对麻风病和multiple myeloma（多发性骨髓瘤）有效——肿瘤细胞依赖过度的血管生成来存活。
- 现已获 FDA 批准用于麻风病和多发性骨髓瘤的治疗，拯救了数千人的生命。
利多卡因
- 标准用途：局部麻醉（牙科、手术切口部位）。
- 一项纳入印度 1,600 名患者的大型试验发现，在手术前 8–10 分钟向乳腺肿瘤周围注射利多卡因，可使五年死亡率降低 29%。
- 该研究发表于《临床肿瘤学杂志》——然而在全球范围内几乎未获临床推广。
- 成本：每次注射仅需几分钱。
- Every Cure 目前正在开展更多实验室研究和证据审查，然后再广泛倡导其推广应用。
秋水仙碱
- 传统用途：痛风（已使用约 3,000 年）。
- 作用机制：具有 anti-inflammatory（抗炎）作用等多种效应。
- 一种改良剂量配方已获 FDA 批准用于心血管二级预防，可降低再次心肌梗死的风险。
- 对既往有心肌梗死病史且合并 diabetes 的患者效果尤为显著。
- 值得关注的是：此次获批需要改良剂量以形成新专利，正是这一条件使临床试验得以真正开展。
帕博利珠单抗（PD-1 抑制剂）
- 最初被开发用于黑色素瘤和肺癌。
- Fajgenbaum 的实验室在 PubMed 上检索时发现了一篇 2013 年的论文，显示 5 例血管肉瘤肿瘤中有 4 例 PD-L1 表达升高。
- 这一实验室发现在发表后的 3 年内，无人将其转化为临床治疗方案。
- 他们为首位已知患者（Michael）使用 PD-1 抑制剂治疗转移性血管肉瘤——Michael 获得了长达九年的缓解，并在不久前亲手将女儿送上婚礼的红毯。
- 帕博利珠单抗目前对约 18% 的血管肉瘤患者有效——将这一曾经预后极差的癌症，转变为约 20% 患者可存活超过一年的可治疗疾病。
TNF 抑制剂与 DADA2
- DADA2：一种罕见遗传病，可导致患者从出生至青少年期间反复发生数十次卒中。
- 一位医生在治疗一名 DADA2 患者时，使用了一种原本用于血管炎的TNF inhibitor（TNF 抑制剂）——该儿童的卒中完全停止。
- 这一发现未能得到系统性传播，历经约 10 年；期间数百名儿童本可获救。
- 如今，TNF 抑制剂已成为 DADA2 的标准治疗方案，在全球范围内阻止了患儿的卒中发作。
托珠单抗（IL-6 抑制剂）
- 由日本的 Dr. Kazu Yoshizaki 专门针对 Castleman 病开发。
- 在日本获批用于 Castleman 病；后被再利用并在美国获批用于rheumatoid arthritis（类风湿关节炎）及其他自身免疫性疾病。
- 对约三分之一的 Castleman 病患者有效。
DFMO 与 Bachmann-Bupp 综合征
- Bachmann-Bupp 综合征：一种罕见遗传病，可导致 ODC1 酶水平升高，患儿因此需依赖鼻饲管进食、卧床不起。
- DFMO 最初被开发用于治疗非洲昏睡病，是 ODC1 的共价结合剂。
- 若早期开始用药，患儿可拔除饲管并显著恢复功能。
Fajgenbaum 的个人求医历程
- 在宾夕法尼亚大学医学院三年级时，被诊断为特发性多中心型 Castleman 病（iMCD）。
- 症状：淋巴结肿大、严重疲劳、腹痛、踝部积液。
- 病情最危重时：因积液体重增加约 100 磅，左眼出现一过性失明（视网膜出血），需每日输注红细胞和血小板，并接受透析治疗。
- 25 岁时被施以临终祈祷（last rites）。
- 经历了七种化疗方案（包括阿霉素、环磷酰胺、依托泊苷、硼替佐米、恩扎卢胺、利妥昔单抗等）才达到缓解。
- 共经历五次濒死事件。
English Original 英文原文
How A Doctor Cured His Own Terminal Disease | Dr. David Fajgenbaum
Summary
Dr. David Fajgenbaum, a professor of translational medicine at the University of Pennsylvania, shares how he nearly died five times from a rare immune disorder called Castleman disease before discovering a treatment by systematically searching existing approved drugs. His experience revealed a massive blind spot in medicine: thousands of approved drugs have untapped therapeutic potential for diseases beyond their original indication, yet no systematic effort exists to identify and deploy these repurposed treatments. He now runs a nonprofit called Every Cure to solve this problem at scale.
Key Takeaways
- 4,000 FDA-approved drugs exist for ~4,000 diseases, but there are still 14,000 diseases with no approved treatment — and 80% of those drugs are already generic with no financial incentive to explore new uses.
- The average small molecule drug binds 20–30 different proteins in the body, meaning most drugs are already doing far more than what they’re approved for.
- Aspirin has been shown to reduce colon cancer recurrence, particularly in patients with mutations in the mTOR pathway, yet this is rarely applied in clinical practice.
- Lidocaine injected around breast tumors 8–10 minutes before surgery showed a 29% reduction in five-year mortality in a 1,600-patient Indian trial — yet has seen almost no clinical uptake.
- Colchicine (traditionally used for gout) has demonstrated substantial reduction in cardiovascular disease risk in patients who have had a prior heart attack, especially those with diabetes.
- Drug repurposing is systematically neglected because once a drug goes generic, no company is financially incentivized to fund trials for new indications.
- TNF inhibitors were found to stop strokes in children with the rare disease DADA2 — but it took years for this knowledge to spread, during which hundreds of children died.
- Patients should actively connect with disease advocacy organizations, seek the world’s leading expert in their condition, and always ask whether alternative or off-label treatments exist elsewhere in the world.
- Sleep deprivation may trigger dangerous cytokine storms — mouse studies showed sleep-deprived mice died from immune overactivation, including elevated interleukin-6, a key cytokine in Castleman disease.
- Fajgenbaum’s nonprofit Every Cure uses AI and biomedical knowledge graphs to systematically match every drug to every disease and is currently running nine active repurposing programs.
Detailed Notes
The Core Problem: Drug Repurposing Is Broken
- There are 4,000 FDA-approved drugs and approximately 18,000 known human diseases.
- Most drugs impact 40+ biological pathways, but are approved and studied for only one or two.
- Once drugs become generic, all pharmaceutical R&D stops — no company will fund large trials for new indications because profits are too low.
- The result: potentially life-saving treatments sit unused, and patients die from “untreatable” diseases that already have solutions hiding in a CVS pharmacy.
- Drug companies do repurpose drugs before patent expiration, but typically into the same disease with a slightly modified formulation, not into genuinely new conditions.
Notable Examples of Drug Repurposing
Aspirin
- Known use: pain relief, blood thinning, heart attack prevention.
- Lesser-known use: reduces risk of colon cancer recurrence, particularly in patients with mTOR pathway mutations.
- Despite published evidence, this use is not standard practice.
Viagra (sildenafil) / Cialis (tadalafil)
- Sildenafil was originally developed for heart disease, then repurposed for erectile dysfunction.
- Also repurposed for pediatric pulmonary hypertension — children who couldn’t get adequate blood flow to their lungs can now live normal lives on sildenafil.
- Tadalafil was initially developed for prostate health and circulation, then later found to treat erectile dysfunction.
Thalidomide
- Originally developed as an anti-nausea drug for pregnant women.
- Caused catastrophic birth defects (limb malformation) due to its anti-angiogenic properties — it blocks blood vessel growth.
- That same mechanism was later found effective against leprosy and multiple myeloma, where tumor cells depend on excess blood vessel formation.
- Now FDA-approved for both leprosy and multiple myeloma, saving thousands of lives.
Lidocaine
- Standard use: local anesthetic (dentistry, surgery incision sites).
- A large trial of 1,600 patients in India found that injecting lidocaine around a breast tumor 8–10 minutes before surgery resulted in a 29% reduction in five-year mortality.
- Published in the Journal of Clinical Oncology — yet almost no clinical uptake worldwide.
- Cost: pennies per injection.
- Every Cure is conducting additional lab work and evidence review before broadly advocating its adoption.
Colchicine
- Traditional use: gout (has been used for ~3,000 years).
- Mechanism: anti-inflammatory effects, among others.
- A modified dose formulation received FDA approval for secondary cardiovascular prevention — reducing risk of recurrent heart attacks.
- Particularly effective in patients with prior heart attack and diabetes.
- Challenge: required a modified dose to generate a new patent, which is what enabled the clinical trials to actually happen.
Pembrolizumab (PD-1 inhibitor)
- Originally developed for melanoma and lung cancer.
- Fajgenbaum’s lab searched PubMed and found a 2013 paper showing 4 of 5 angiosarcoma tumors had elevated PD-L1 expression.
- No one had translated this laboratory finding into a clinical treatment in the 3 years since publication.
- They treated the first known patient (Michael) with a PD-1 inhibitor for metastatic angiosarcoma — he entered nine-year remission and recently walked his daughter down the aisle.
- Pembrolizumab now works in approximately 18% of angiosarcoma patients — transforming a uniformly fatal cancer into one where ~20% of patients survive beyond one year.
TNF Inhibitors and DADA2
- DADA2: rare genetic condition causing dozens of strokes from birth through teenage years.
- A physician treating a DADA2 patient used a leftover TNF inhibitor (made for vasculitis) — the child’s strokes stopped completely.
- The discovery wasn’t systematically shared for ~10 years; hundreds of children died who could have been saved.
- Now, TNF inhibitors are the standard treatment for DADA2, stopping strokes in children worldwide.
Tocilizumab (IL-6 inhibitor)
- Developed by Dr. Kazu Yoshizaki in Japan specifically for Castleman disease.
- Approved in Japan for Castleman’s; later repurposed and approved in the U.S. for rheumatoid arthritis and other autoimmune diseases.
- Works in approximately one-third of Castleman disease patients.
DFMO for Bachmann-Bupp Syndrome
- Bachmann-Bupp syndrome: rare genetic disorder causing elevated ODC1 enzyme, leaving children tube-fed and bed-bound.
- DFMO, a drug originally made for African sleeping sickness, is a covalent binder to ODC1.
- When started early, children have feeding tubes removed and gain significant function.
Fajgenbaum’s Personal Medical Journey
- Diagnosed with idiopathic multicentric Castleman disease (iMCD) during his third year of medical school at Penn.
- Symptoms: enlarged lymph nodes, severe fatigue, abdominal pain, fluid retention in ankles.
- At peak illness: gained ~100 pounds of fluid, experienced temporary blindness in his left eye (retinal hemorrhage), required daily transfusions of red blood cells and platelets, placed on dialysis.
- Had last rites read at age 25.
- Required seven chemotherapies (Adriamycin, Cytoxan, Etoposide, Velcade, Enzalutamide, Rituxan, and others) to achieve remission.
- Experienced five near-death episodes