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← Open-source cancer research

How does cancer know it's cancer? At Jay Bradner's lab, they found a molecule that might hold the answer, JQ1 -- and instead of patenting JQ1, they published their findings and mailed samples to 40 other labs to work on. An inspiring look at the open-source future of medical research.

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Showing Revision 4 created 06/03/2016 by Krystian Aparta.

  1. I moved to Boston
    10 years ago from Chicago,
  2. with an interest in cancer
    and in chemistry.
  3. You might know that chemistry
    is the science of making molecules
  4. or, to my taste,
  5. new drugs for cancer.
  6. And you might also know that,
    for science and medicine,
  7. Boston is a bit of a candy store.
  8. You can't roll a stop sign in Cambridge
    without hitting a graduate student.
  9. The bar is called the Miracle of Science.
  10. The billboards say "Lab Space Available."
  11. And it's fair to say
    that in these 10 years,

  12. we've witnessed absolutely the start
    of a scientific revolution --
  13. that of genome medicine.
  14. We know more about the patients
    that enter our clinic now
  15. than ever before.
  16. And we're able, finally,
    to answer the question
  17. that's been so pressing for so many years:
  18. Why do I have cancer?
  19. This information
    is also pretty staggering.
  20. You might know that, so far,
    in just the dawn of this revolution,
  21. we know that there are perhaps
    40,000 unique mutations
  22. affecting more than 10,000 genes,
  23. and that there are 500 of these genes
    that are bona-fide drivers,
  24. causes of cancer.
  25. Yet comparatively,

  26. we have about a dozen
    targeted medications.
  27. And this inadequacy of cancer medicine
  28. really hit home when my father
    was diagnosed with pancreatic cancer.
  29. We didn't fly him to Boston.
  30. We didn't sequence his genome.
  31. It's been known for decades
    what causes this malignancy.
  32. It's three proteins: ras, myc, p53.
  33. This is old information
    we've known since about the 80s,
  34. yet there's no medicine I can prescribe
  35. to a patient with this
    or any of the numerous solid tumors
  36. caused by these three ...
  37. Horsemen of the Apocalypse that is cancer.
  38. There's no ras, no myc, no p53 drug.
  39. And you might fairly ask: Why is that?

  40. And the very unsatisfying
    yet scientific answer is:
  41. it's too hard.
  42. That for whatever reason,
  43. these three proteins have entered
    a space, in the language of our field,
  44. that's called the undruggable genome --
  45. which is like calling
    a computer unsurfable
  46. or the Moon unwalkable.
  47. It's a horrible term of trade.
  48. But what it means
  49. is that we've failed to identify
    a greasy pocket in these proteins,
  50. into which we, like molecular locksmiths,
  51. can fashion an active, small,
    organic molecule or drug substance.
  52. Now, as I was training
    in clinical medicine

  53. and hematology and oncology
    and stem-cell transplantation,
  54. what we had instead,
  55. cascading through the regulatory
    network at the FDA,
  56. were these substances:
  57. arsenic,
  58. thalidomide,
  59. and this chemical derivative
    of nitrogen mustard gas.
  60. And this is the 21st century.
  61. And so, I guess you'd say,
  62. dissatisfied with the performance
    and quality of these medicines,
  63. I went back to school, in chemistry,
  64. with the idea that perhaps by learning
    the trade of discovery chemistry
  65. and approaching it in the context
    of this brave new world
  66. of the open source,
  67. the crowd source,
  68. the collaborative network
    that we have access to within academia,
  69. that we might more quickly bring
    powerful and targeted therapies
  70. to our patients.
  71. And so, please consider
    this a work in progress,

  72. but I'd like to tell you today a story
  73. about a very rare cancer
    called midline carcinoma,
  74. about the undruggable protein target
    that causes this cancer,
  75. called BRD4,
  76. and about a molecule developed at my lab
    at Dana-Farber Cancer Institute,
  77. called JQ1,
  78. which we affectionately named for Jun Qi,
  79. the chemist that made this molecule.
  80. Now, BRD4 is an interesting protein.
  81. You might ask: with all the things
    cancer's trying to do to kill our patient,

  82. how does it remember it's cancer?
  83. When it winds up its genome,
  84. divides into two cells and unwinds again,
  85. why does it not turn
    into an eye, into a liver,
  86. as it has all the genes
    necessary to do this?
  87. It remembers that it's cancer.
  88. And the reason is that cancer,
    like every cell in the body,
  89. places little molecular bookmarks,
  90. little Post-it notes,
  91. that remind the cell, "I'm cancer;
    I should keep growing."
  92. And those Post-it notes involve this
    and other proteins of its class --
  93. so-called bromodomains.
  94. So we developed an idea, a rationale,
  95. that perhaps if we made a molecule
  96. that prevented
    the Post-it note from sticking
  97. by entering into the little pocket
  98. at the base of this spinning protein,
  99. then maybe we could convince cancer cells,
  100. certainly those addicted
    to this BRD4 protein,
  101. that they're not cancer.
  102. And so we started to work on this problem.

  103. We developed libraries of compounds
  104. and eventually arrived
    at this and similar substances
  105. called JQ1.
  106. Now, not being a drug company,
  107. we could do certain things,
    we had certain flexibilities,
  108. that I respect that a pharmaceutical
    industry doesn't have.
  109. We just started mailing it to our friends.
  110. I have a small lab.
  111. We thought we'd just send it to people
    and see how the molecule behaves.
  112. We sent it to Oxford, England,
  113. where a group of talented
    crystallographers provided this picture,
  114. which helped us understand exactly
    how this molecule is so potent
  115. for this protein target.
  116. It's what we call a perfect fit
    of shape complementarity,
  117. or hand in glove.
  118. Now, this is a very rare cancer,

  119. this BRD4-addicted cancer.
  120. And so we worked with samples of material
  121. that were collected by young pathologists
    at Brigham and Women's Hospital.
  122. And as we treated these cells
    with this molecule,
  123. we observed something really striking.
  124. The cancer cells --
  125. small, round and rapidly dividing,
  126. grew these arms and extensions.
  127. They were changing shape.
  128. In effect,
  129. the cancer cell
    was forgetting it was cancer
  130. and becoming a normal cell.
  131. This got us very excited.

  132. The next step would be to put
    this molecule into mice.
  133. The only problem was there's no
    mouse model of this rare cancer.
  134. And so at the time
    we were doing this research,
  135. I was caring for a 29-year-old
    firefighter from Connecticut
  136. who was very much at the end of life
  137. with this incurable cancer.
  138. This BRD4-addicted cancer
    was growing throughout his left lung.
  139. And he had a chest tube in
    that was draining little bits of debris.
  140. And every nursing shift,
    we would throw this material out.
  141. And so we approached this patient
  142. and asked if he would collaborate with us.
  143. Could we take this precious
    and rare cancerous material
  144. from this chest tube
  145. and drive it across town
    and put it into mice
  146. and try to do a clinical trial
    at a stage that with a prototype drug,
  147. well, that would be, of course, impossible
  148. and, rightly, illegal to do in humans.
  149. And he obliged us.
  150. At the Lurie Family Center
    for Animal Imaging,
  151. our colleague, Andrew Kung,
    grew this cancer successfully in mice
  152. without ever touching plastic.
  153. And you can see this PET scan
    of a mouse -- what we call a pet PET.

  154. The cancer is growing
  155. as this red, huge mass
    in the hind limb of this animal.
  156. And as we treat it with our compound,
  157. this addiction to sugar,
  158. this rapid growth, faded.
  159. And on the animal on the right,
  160. you see that the cancer was responding.
  161. We've completed, now, clinical trials
  162. in four mouse models of this disease.
  163. And every time, we see the same thing.
  164. The mice with this cancer
    that get the drug live,
  165. and the ones that don't rapidly perish.
  166. So we started to wonder,

  167. what would a drug company
    do at this point?
  168. Well, they probably
    would keep this a secret
  169. until they turn the prototype drug
  170. into an active pharmaceutical substance.
  171. So we did just the opposite.
  172. We published a paper
    that described this finding
  173. at the earliest prototype stage.
  174. We gave the world the chemical
    identity of this molecule,
  175. typically a secret in our discipline.
  176. We told people exactly how to make it.
  177. We gave them our email address,
  178. suggesting that if they write us,
  179. we'll send them a free molecule.
  180. (Laughter)

  181. We basically tried to create
    the most competitive environment

  182. for our lab as possible.
  183. And this was, unfortunately, successful.
  184. (Laughter)

  185. Because now, we've shared this molecule,

  186. just since December of last year,
  187. with 40 laboratories in the United States
  188. and 30 more in Europe --
  189. many of them pharmaceutical companies,
  190. seeking now to enter this space,
  191. to target this rare cancer
    that, thankfully right now,
  192. is quite desirable
    to study in that industry.
  193. But the science that's coming back
    from all of these laboratories
  194. about the use of this molecule
  195. has provided us insights
    we might not have had on our own.
  196. Leukemia cells treated with this compound
  197. turn into normal white blood cells.
  198. Mice with multiple myeloma,
  199. an incurable malignancy
    of the bone marrow,
  200. respond dramatically
  201. to the treatment with this drug.
  202. You might know that fat has memory.
  203. I'll nicely demonstrate that for you.
  204. (Laughter)

  205. In fact, this molecule

  206. prevents this adipocyte,
    this fat stem cell,
  207. from remembering how to make fat,
  208. such that mice on a high-fat diet,
  209. like the folks
    in my hometown of Chicago --
  210. (Laughter)

  211. fail to develop fatty liver,

  212. which is a major medical problem.
  213. What this research taught us --

  214. not just my lab, but our institute,
  215. and Harvard Medical School
    more generally --
  216. is that we have unique
    resources in academia
  217. for drug discovery;
  218. that our center, which has tested
    perhaps more cancer molecules
  219. in a scientific way
  220. than any other,
  221. never made one of its own.
  222. For all the reasons you see listed here,
  223. we think there's a great
    opportunity for academic centers
  224. to participate in this earliest,
    conceptually tricky
  225. and creative discipline
  226. of prototype drug discovery.
  227. So what next?

  228. We have this molecule,
    but it's not a pill yet.
  229. It's not orally bioavailable.
  230. We need to fix it so we can
    deliver it to our patients.
  231. And everyone in the lab,
  232. especially following the interaction
    with these patients,
  233. feels quite compelled
    to deliver a drug substance
  234. based on this molecule.
  235. It's here where I'd say
  236. that we could use your help
    and your insights,
  237. your collaborative participation.
  238. Unlike a drug company,
    we don't have a pipeline
  239. that we can deposit these molecules into.
  240. We don't have a team
    of salespeople and marketeers
  241. to tell us how to position
    this drug against the other.
  242. What we do have is the flexibility
    of an academic center
  243. to work with competent, motivated,
  244. enthusiastic, hopefully well-funded people
  245. to carry these molecules
    forward into the clinic
  246. while preserving our ability
    to share the prototype drug worldwide.
  247. This molecule will soon leave our benches

  248. and go into a small start-up company
    called Tensha Therapeutics.
  249. And, really, this is the fourth
    of these molecules
  250. to kind of "graduate"
    from our little pipeline
  251. of drug discovery,
  252. two of which -- a topical drug
    for lymphoma of the skin
  253. and an oral substance for the treatment
    of multiple myeloma --
  254. will actually come to the bedside
    for the first clinical trial
  255. in July of this year -- for us,
    a major and exciting milestone.
  256. I want to leave you with just two ideas.
  257. The first is: if anything is unique
    about this research,
  258. it's less the science than the strategy.
  259. This, for us, was a social experiment --
  260. an experiment in "What would happen
    if we were as open and honest
  261. at the earliest phase
    of discovery chemistry research
  262. as we could be?"
  263. This string of letters and numbers

  264. and symbols and parentheses
  265. that can be texted, I suppose,
  266. or Twittered worldwide,
  267. is the chemical identity
    of our pro compound.
  268. It's the information that we most need
    from pharmaceutical companies,
  269. the information on how these early
    prototype drugs might work.
  270. Yet this information is largely a secret.
  271. And so we seek, really, to download
  272. from the amazing successes
    of the computer-science industry,
  273. two principles -- that of open source
    and that of crowdsourcing --
  274. to quickly, responsibly accelerate
    the delivery of targeted therapeutics
  275. to patients with cancer.
  276. Now, the business model
    involves all of you.

  277. This research is funded by the public.
  278. It's funded by foundations.
  279. And one thing I've learned in Boston
  280. is that you people will do anything
    for cancer, and I love that.
  281. You bike across the state,
    you walk up and down the river.
  282. (Laughter)

  283. I've never seen, really, anywhere,

  284. this unique support for cancer research.
  285. And so I want to thank you
  286. for your participation, your collaboration
  287. and most of all,
  288. for your confidence in our ideas.
  289. (Applause)