• Ryon Graf

The Future was Yesterday at the 25th Usha Mahajani Symposium on Cancer Genomics at the Salk Institut

10 September 2013

Yesterday I had the pleasure of attending the 25th Usha Mahajani Symposium at the Salk Institute. This year’s theme was Cancer Genomics, an extremely hot area of research right now. It attracted an all-star cast of international bioinformaticians with “TED-quality” presentations, as referred to by a colleague.

Kenna Shaw is the (now-former) director of The Cancer Genome Atlas project (I’ve often wondered if the acronym TCGA was not perhaps a tad too perfect) and gave a great talk on the progress of the database and some of the fundamental insights into cancer biology already discovered in the process. They are approaching their goal of 500 cancer genomes per cancer type* with matching mRNA, copy number variation, survival data and more for both tumor tissue and matching normal tissue (usually blood). My favorite browser for this data is the cBioPortal from Sloan-Kettering.

*I find it somewhat ironic that TCGA data is organized by gross histological subtype – using a system of organization that it is simultaneously making obsolete.

It was not originally clear to me that only malignant tumor cases are represented. None of the patients had carcinomas in situ. Also, all of the patients were treatment-naiive. The data has not been affected by selection pressures of chemotherapy.

One of the best messages put forth by Shaw in her dense, frenetic paced talk was the need to look not just at genomic data, but all of the -omics, and the lengths her groups went through to get complete data on many fronts for these cancer patient samples.

Rene Bernards gave a fantastic talk outlining a resistance mechanism to vemurafenib, a BRAF V600E inhibitor that became available for melanoma a few years ago. In what seemed very odd at first, the upstream kinase EGFR was upregulated to escape BRAF / MEF / ERK blockade, which lead to PI3K pathway activation. The takeaway messages from his talk were twofold for me:

1) Cellular circuitry is much more redundant than we intuitively think and we’ve likely just begun to uncover many of the resistance pathways to targeted chemotherapy. 2) Understanding these most common resistance pathways might allow complementary blockade through combinational therapy (a PI3K or mTOR inhibitor paired with vemurafenib, for instance).

Atul Butte produced a vision of what computational biological labs (and garage biotech startups) might look like in the future. He stressed the point that it’s becoming more and more possible to “outsource everything but the questions.” He then told a story of his own research projects that was more about the process than the result, namely the use of several powerful pharmaceutical research experiment vendors like Assay Depot combined with (shockingly free) resources like the massive genome array database Gene Expression Omnibus and Chem Pub, and when topped off with the (yes, free) central clinical trials database IMMPort. Butte produces a vision (business model?) for someone with the appropriate computational skillset to create an academic research lab (or garage biotech company) with minimal overhead.

Razelle Kurzrock‘s presentation is worthy of its own follow-up article and commentary. She stressed that we absolutely need to change the way we conduct early stage clinical trials for targeted therapies. Toward that end, a few main messages from her talk:

1) We are shooting ourselves in the foot trying out new targeted therapies in patients that are already refractory for disease. She made many parallels to the CML / Imatinib revolution that resulted from treating early-stage patients with BCR-ABL blockade.

2) We need to organize clinical trials around “molecular hubs” (i.e. the EGFR / RAF / MEK / ERK / PI3K / mTOR axis) not necessarily tumor-tissue-of-origin type, and validate molecular hub targeting strategies, not specific drugs.

3) We need to determine rules of thumb for safe drug combinations, since the specific tailored combinations received by patients in her vision might might be rare and not vetted by thousands of patients getting the same tailored combinations.

Overall I had a great time at the symposium and look forward to attending next year.

Ryon