The transition to genomically driven oncology has begun, catalyzed in part by efforts to rationally design effective therapies targeting the specific molecular aberrations on which individual tumors depend. This has led, inexorably, to the prospective clinical sequencing of patients with active disease to guide their cancer care. Nevertheless, a fundamental gap remains. The shift toward larger panel and whole exome sequencing has led to the identification of increasing numbers of somatic mutations in even presumed actionable cancer genes, the vast majority of which are in the so-called long right tail and lack biological or clinical validation. This significantly impairs our ability to use findings generated by prospective profiling to guide patient care. We have recently shown that such long-tail driver mutations can be the genetic basis of extraordinary responses to systemic cancer therapy. We went on to show that a systematic survey utilizing population-scale cancer genome data coupled to computational methodologies reveals similar long-tail drivers of both biological and therapeutic significance. These findings underscore the importance of long-tail driver mutations in cancer, but without a systematic approach for rapidly prioritizing and functionally and clinically validating these somatic mutations, the gap in our understanding of the clinically actionable genome will widen. We propose to overcome this urgent clinical challenge by establishing a robust and sophisticated framework for elucidating novel driver mutations in the long tail. We will first establish a comprehensive computational framework that identifies and prioritizes long-tail driver mutations that leverages not only population-scale data but integrates orthogonal measures of selection. We will then apply these methods to a cohort of greater than 50,000 prospectively sequenced active cancer patients at our Center, all possessing detailed clinical, outcome, and treatment response data, results from which can lead to the enrollment of patients on genotype-directed clinical trials. Finally, we will perform functional studies of novel long-tail driver mutations revealed by these analyses in genes for which there is an open basket study at our institution, thereby establishing a co-clinical framework by which laboratory functional validation can be paired with patient treatment response. Together, these studies seek to establish a computational-experimental framework for identifying functional mutations in the long tail that expand the treatment options for molecularly defined populations of cancer patients.

Public Health Relevance

Prospective clinical sequencing is poised to transform the care of cancer patients. Yet, the function and effect of the vast majority of mutations we identify in these patients is unknown, which limits our ability to act clinically. To overcome this challenge, we propose an innovative multidisciplinary approach to efficiently computationally prioritize, experimentally validate, and clinically cross-validate long tail driver mutations to optimize the treatment of patients with lethal cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA204749-01A1
Application #
9238972
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Ossandon, Miguel
Project Start
2017-02-06
Project End
2022-01-31
Budget Start
2017-02-06
Budget End
2018-01-31
Support Year
1
Fiscal Year
2017
Total Cost
$784,156
Indirect Cost
$326,656
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
Research Institutes
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Chang, Matthew T; Penson, Alexander V; Desai, Neil B et al. (2017) Small cell carcinomas of the bladder and lung are characterized by a convergent but distinct pathogenesis. Clin Cancer Res :
Zehir, Ahmet; Benayed, Ryma; Shah, Ronak H et al. (2017) Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 23:703-713
Gao, Jianjiong; Chang, Matthew T; Johnsen, Hannah C et al. (2017) 3D clusters of somatic mutations in cancer reveal numerous rare mutations as functional targets. Genome Med 9:4
Burgess, Michael R; Hwang, Eugene; Mroue, Rana et al. (2017) KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer. Cell 168:817-829.e15
Chang, Matthew T; Bhattarai, Tripti Shrestha; Schram, Alison M et al. (2017) Accelerating Discovery of Functional Mutant Alleles in Cancer. Cancer Discov :
Hyman, David M; Smyth, Lillian M; Donoghue, Mark T A et al. (2017) AKT Inhibition in Solid Tumors With AKT1 Mutations. J Clin Oncol 35:2251-2259
Yao, Zhan; Yaeger, Rona; Rodrik-Outmezguine, Vanessa S et al. (2017) Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature 548:234-238
Drilon, Alexander; Nagasubramanian, Ramamoorthy; Blake, James F et al. (2017) A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. Cancer Discov 7:963-972
Hyman, David M; Taylor, Barry S; Baselga, José (2017) Implementing Genome-Driven Oncology. Cell 168:584-599