Will Hendricks

Will Hendricks Ph.D.

Assistant Professor
Integrated Cancer Genomics Division

Will Hendricks Ph.D.

Despite decades of progress in the clinical management of cancer and amidst recent innovations in genomics-guided medicine, we are still incapable of curing most patients who are diagnosed with advanced cancers. Our laboratory focuses on shifting paradigms in cancer treatment to enable cures through programs at the intersection of personalized medicine and comparative genomics.

Dissecting biological determinants of therapeutic vulnerability in human melanoma through integrated analysis of genomic data.  As part of the Stand Up to Cancer and Melanoma Research Alliance Dream Team, we are directing a clinical trial evaluating the hypothesis that genomics-guided drug selection can outperform physician-guided treatment in melanoma patients. Our laboratory is also working to characterize the biology of therapeutic sensitivity in melanoma cell lines through integrated analysis of comprehensive genomic, proteomic, and therapeutic data (including exome sequencing, array CGH, gene expression profiling, proteomic profiling, and high-throughput RNAi and drug screens). Hypotheses tested in vitro are contextualized through ongoing genomic analysis conducted in patient samples collected during the course of the genomics-guided clinical trial and alongside data available through public portals such as the TCGA.

Mapping canine cancer landscapes for identification of actionable targets to guide comparative clinical trials.  The work described above will support development of targeted inhibitors and combinations to spur further survival gains in human melanoma. Yet, testing novel agents, combinations, and dosing schedules can be challenging in human clinical trials due to their restrictive nature. Thus, we have turned to comparative oncology where it has long been recognized that extraordinary potential lies in aligning studies of sporadic cancers in pet dogs with drug development in human cancers. To this end, we have mapped the genomic landscape of canine mucosal melanoma, a common and lethal cancer in dogs that is equally deadly, but far less common, in humans. Integrated analysis has revealed genomic landscapes that resemble the human disease while also identifying novel therapeutically-relevant mutations that are reshaping our understanding of the human disease. We are now pursuing integrated comparative analysis of additional tumor types while these data are informing the development of comparative veterinary trials.

Integrating genomic and therapeutic analyses of pediatric cancers.  We have recently discovered frequent inactivating mutations and concomitant loss of the tumor suppressor SMARCA4 in the majority of cases of a rare cancer that afflicts girls and young women - small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). This mutation occurs amidst an otherwise stable cancer genome and thus provides a unique opportunity to study an isolated driver mutation of relevance to more genomically complex cancers with higher mutation rates (such as melanoma). More importantly, it provides a clear target in an extremely rare cancer for our ongoing pursuit of an empirically-derived therapeutic option for these underserved patients.

Recurrent somatic inactivating PTPRJ mutations and key dysregulated pathways identified in canine melanoma by integrated genomic analysis. Hendricks W, Zismann V, Legendre C, Tembe W, Kiefer J, Button B, Bittner M, Liang W, Stark M, Poorman K, LoRusso P, Berry D, Ruhe A, Froman R, Duesbury N, Neff M, Hewitt S, Huentelman M, Breen M, Craig D, Hayward N, Khanna C, Davis B, Sekulic A, Trent J. Nature Communications. Invited manuscript in preparation. 

Dual loss of the SWI/SNF complex ATPase SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcemic type. Karnezis A, Wang Y, Ramos P, Hendricks W, Oliva E, D’Angelo E, Prat J, Nucci MR, Nielsen TO, Chow C, Leung S, Kommoss F, Kommoss S, Fabiana A, Da Silva L, Ronnett BM, Rabban JT, Bowtell DD, Weissman BE, Trent JM, Gilks CB, Huntsman DG. The Journal of Pathology. In Press.

Loss of the tumor suppressor SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)Ramos P, Karnezis A, Hendricks W,
Wang Y, Tembe W, Zismann V, Legendre C, Liang W, Russell M, Craig D, Farley J, Monk B, Anthony S, Sekulic A, Cunliffe H, Huntsman D, Trent JM. Rare Diseases. 2014, Nov; 2. 

Formulating the magic bullet: barriers to clinical translation of nanoparticle cancer gene therapy. Hendricks W, Yang J, Sur S & Zhou S. Nanomedicine. 2014, June; 9:1121-1124. 

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