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Building A Research Community: RAS/RAF/EGFR @ AACR

Building A Research Community: RAS/RAF/EGFR @ AACR. Justin Guinney, PhD Charles Ferte, MD Alex Pico, PhD Stephen Friend MD, PhD Frank McCormick, PhD. Objective: strengthen the RAS-RAF-EGFR community @ AACR. Encourage novel collaborations through identification of related research.

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Building A Research Community: RAS/RAF/EGFR @ AACR

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  1. Building A Research Community: RAS/RAF/EGFR @ AACR Justin Guinney, PhD Charles Ferte, MD Alex Pico, PhD Stephen Friend MD, PhD Frank McCormick, PhD

  2. Objective: strengthen the RAS-RAF-EGFR community @ AACR Encourage novel collaborations through identification of related research “Beyond the abstract”: challenges and needs in the community

  3. 2012/13 AACR “Interactome” • RAS-RAF-EGFR selected abstracts • 2013: 793 abstracts • 2012: 595 abstracts • 8813 (unique) authors

  4. 2013 vs. 2012 comparison

  5. Interactome Methods From many thousand of abstracts, identified 1300+ RAS-RAF-EGFR abstracts using key words matching Parsed abstract text/title to generate large document-word matrix Applied text mining normalization methods, such as white space and stop word removal, and stemming Applied “document frequency – inverse word frequency” normalization Generated abstract similarity matrix using cosine metric Generated global hierarchical model using Affinity Message Passing algorithm

  6. Interactome Demo http://aacr.sagebase.org

  7. Survey explores “Beyond the abstract” (challenges & needs in the community) Q1: “What do you consider to be one of the most exciting or unexpected recent developments…?” Q2: “Do you have any negative results and/or unexpected observations that you are willing to share...?” Q3: “What is a pressing question…?” 396 responses to open-ended questions !

  8. Survey results publicly available @ http://aacr.sagebase.org/survey

  9. Survey question 1 Q1: “What do you consider to be one of the most exciting or unexpected recent developments…?”

  10. What is the most exciting recent result or paper related to RAS RAF EGFR ? 333 open-ended responses / 396 participants (84%) !!! ~ 50% responders directly cited publications. ~ 50 responses included >2 references or results ! We grouped the responses according to specific (subjective) topics (n=29)

  11. What is the most exciting recent result related to RAS RAF EGFR ?

  12. What are the top most frequently cited “thrilling results” ?

  13. “Resistance mechanisms to EGFR RAS RAF targeting” and “Paradoxical effect of BRAF inhibitors on MAPK signaling” (> 100 times among responses)

  14. “Role of wild type RAS in RAS mutant cells” (> 20 times among responses)

  15. “RAS oncogene is not enough for pathway activation” (> 15 times among responses)

  16. “new opportunities for targeting RAF: MEK-independent role of CRAF; RAF dimerization” (>15 times among responses)

  17. Overall, these 7 references directly mentioned or overlapped with ~ 50% of the responses ! This is a direct example showing how the RAS-RAF-EGFR community at the AACR annual meeting is thrilled by the same results and is dynamic !

  18. Survey question 2 Q2: “Do you have any unexpected and/or negative observations that you are willing to share...?”

  19. Negative results 126 responses out of 396 questionnaires (31%) Many responses explicitly stated that negative results should get more awareness “I think the idea of sharing our collective research will provide a faster solution to the disease we are trying to control. Great idea on the session!” “i don’t have any to share right now, but i think negative results are as important as positive results”

  20. Negative results (1): Non reproducible results, contextual issues, ... “We have been unable to find that HER2 is resistant to activation-induced endocytosis.” “We are among the groups that have failed to validate TBK1, STK33 and other potential targets described in the literature as synthetic lethals with KRASm. Most recent data concern the MNK kinases and a failure to impact EIF4E mediated translation.” “Many published anti-Ras synthetic lethal modulators do not demonstrate activated K-Ras dependent inhibitory activity in our 3D assay system.” “In pancreatic cancer cell lines, when silencing KRAS using siRNA knock-down, I have seen no effects on proliferation or viability....in contrast to some publications showing apparent "KRAS addiction"

  21. Negative results (2): paradoxical effects (hypothesis-generating results) “Unexpected: inhibition of EGFR by high dose EGF” “I have found that delivery of K-Ras can have a negative impact on cell proliferation in Caco2 cells. This is unexpected as Ras is oncogenic and should increase proliferation. Any insight about negative effects of Ras on cell growth would be helpful.” “Erlotinib accelerates KRAS mutant lung tumour growth in mouse KRAS LA2 model. Why? Is this same issue as seen in early clinical trials with erlotinib with KRAS mutant lung cancer patients. What is mechanism for this?”

  22. Unexpected results = hypothesis generating findings. The RAS RAF EGFR survey enables further collaborations !

  23. Survey question 3 “What is a pressing question related to RAS-RAF-EGFR…?”

  24. Is RAS druggable: myth or fact “As a younger researcher I've been told many times that none of the RAS genes are 'druggable'. When I've inquired about the reasons I'm usually met with a stare and a response that 'everyone knows that'. I've come to accept that RAS genes are not druggable as dogma but wish someone could point me to a definitive review of the complexities and vagaries of why this is true. If such a resource does not exist, I wish those with intimate knowledge of the subject would create a clear, concise history on the un-drugability of H-RAS, N-RAS and K-RAS.” Why are there no RAS drugs? “Will anyone consider revisiting the question of whether the mutant KRAS protein could be therapeutically targeted directly?” “Why is finding a Ras inhibitor so difficult?” “why is RAS so difficult to target and what are the most promising approaches?” “Why is RAS so difficult to target? Why didn't farnesyl transferase inhibitors work clinically?” “Why are there no effective Ras inhibitors yet?” “Is RAS still considered undruggable, even in light of its multiple signaling partners ?”

  25. … but wait “…[the RAS inhibitor] compound does not work in cells as described in their paper” from negative results survey question

  26. Polling Question # 1

  27. Do you feel qualified to answer the following question? Yes or No • Yes, I feel qualified to answer this question. • No, I do not feel qualified to answer this question “The difficulty in targeting the GTP binding to RAS is a consequence of the extremely high affinity of this binding - in the picomolar range. Does this make it impossible to target though? With improved technology and medicinal chemistry can we perhaps succeed with this strategy?” 10 Countdown

  28. Why KRAS and not HRAS (or NRAS) “Why is KRAS, not HRAS, a common oncogene in human cancer?” “Biological differences among three oncogenic Ras genes” “More details regarding the differences in KRAS and NRAS mutations and why some KRAS mutants specifically activate certain downstream pathways vs other KRAS mutants.”

  29. Mammalian KRAS is enriched in rare codons that limit its expression

  30. Polling Question # 2

  31. Do you feel qualified to answer the following question? Yes or No • Yes, I feel qualified to answer this question. • No, I do not feel qualified to answer this question “Why is KRAS, not HRAS, a common oncogene in human cancer?” 10 Countdown

  32. RAS mutation = RAS pathway activation?(and context dependency) “How to monitor the critical downstream mediators of BRAF, CRAF, MEK and ERK in a quantitative fashion to understand relative contribution in a given tumor as well as a measure of molecular response to therapy.” “Ability to truly determine KRASm dependency in vivo” “I am interested in the role that this pathway plays in different tissues leading to cell lines specific sensitivity to inhibition. I would love to discuss a deep genomic analysis of the cell lines used in recent studies (CCLE and Sanger) to understand the "Ras-ness" of the different lines with respect to other gene expression.” how to distinguish wild-type RAS patients from mutants, i.e. how to find patients that will benefit from anti EGFR treatment from those that won't. “Context: What differs about the signal in different tissues” “Why does the same KRAS mutation have distinct biologic functions and predictive value in different tumor types (lung vs. pancreatic vs. colon)?” “Why do some tumors depend on RAS even if RAS is not mutated.”

  33. “RASness”: RAS activation as a continuum in TCGA CRC Unpublished, Sage Bionetworks

  34. Polling Question # 3

  35. Do you feel qualified to answer the following question? Yes or No • Yes, I feel qualified to answer this question. • No, I do not feel qualified to answer this question “How can we distinguish wild-type RAS patients from mutants, i.e. how can we distinguish patients that will benefit from anti EGFR treatment from those that won’t?” 10 Countdown

  36. Can we translate RAS complexity to the bedside?(combination therapy?) “What is its therapeutic utility?” “RAS is more likely to play a more important role as prognostic factor rather than predictive factor for response to therapy with anti-EGFR mAbs” “How effective are the MEK inhibitors on cancers harboring RAS mutation, like pancreatic cancer, CRC?” “Ras has many downstream pathways. If we want to inhbit Ras by drug combinations inhbiting these pathways how many will we need? Is it a feasible approach?” “Is combination of drugs the only way for RAS or BRAF mutant colorectal cancer?”

  37. Polling Question # 4

  38. Do you feel qualified to answer the following question? Yes or No • Yes, I feel qualified to answer this question. • No, I do not feel qualified to answer this question “Is combining existing pathway inhibitors a reasonable approach to overcome resistance or should we be looking at novel drugs with broader kinase activity?” 10 Countdown

  39. Polling Question # 5

  40. Do you feel qualified to answer the following question? Yes or No • Yes, I feel qualified to answer this question. • No, I do not feel qualified to answer this question “The EGFR gene is rarely mutated or amplified in colorectal cancer. Still, it is the only validated target, expressed by cancer cells, in this tumor setting. How is it possible that EGFR signaling is so important in a subset of colorectal cancers, in the absence of any underlying genetic lesion?” 10 Countdown

  41. Polling Question # 6

  42. Do you feel qualified to answer the following question? Yes or No • Yes, I feel qualified to answer this question. • No, I do not feel qualified to answer this question “Why KRAS/BRAF mutations are restricted in specific type of cancers (mainly adenocarcinoma) but not others (squamous cell carcinoma or HCC)?” 10 Countdown

  43. Polling Question # 7

  44. Do you feel qualified to answer the following question? Yes or No • Yes, I feel qualified to answer this question. • No, I do not feel qualified to answer this question “Is phosphorylation of the EGFR in mutated and non-mutated adenocarcinomas random or specific?” 10 Countdown

  45. Polling Question # 8

  46. Do you feel qualified to answer the following question? Yes or No • Yes, I feel qualified to answer this question. • No, I do not feel qualified to answer this question “What other key RAS pathways besides PI3K and MAPk are critical, especially for GI malignancies, where combined PI3K/MEK inhibition has not produced promising results?” 10 Countdown

  47. Polling Question # 9

  48. Do you feel qualified to answer the following question? Yes or No • Yes, I feel qualified to answer this question. • No, I do not feel qualified to answer this question “Do EGFR inhibitors or antibodies have any role to play in treating KRAS mutant tumors?” 10 Countdown

  49. Polling Question # 10

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