Jason Somarelli

Positions:

Assistant Professor in Medicine

Medicine, Medical Oncology
School of Medicine

Assistant Professor

Marine Science and Conservation
Nicholas School of the Environment

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2009

Florida International University

Grants:

Targeting the p38/Snail/PD-L1 axis in hormone-therapy resistance and metastasis

Administered By
Medicine, Medical Oncology
Awarded By
Department of Defense
Role
Principal Investigator
Start Date
End Date

Targeting Convergent Mechanisms of Therapy Resistance, Metastasis, and Immune Evasion with CBP inhibitors

Administered By
Medicine, Medical Oncology
Role
Principal Investigator
Start Date
End Date

Development of Circulating Molecular Predictors of Chemotherapy and Novel Hormonal Therapy Benefit in Men with Metastatic Castration Resistant Prostate Cancer (mCRPC)

Administered By
Medicine, Medical Oncology
Role
Post Doctoral Trainee
Start Date
End Date

Testing the efficacy of AR degrading compounds in enzalutamide-resistant prostate cancer

Administered By
Medicine, Medical Oncology
Role
Principal Investigator
Start Date
End Date

Validation and interrogation of differentially expressed and alternatively spliced genes in African American prostate ca

Administered By
Duke Cancer Institute
Awarded By
Department of Defense
Role
Postdoctoral Associate
Start Date
End Date

Publications:

Molecular Biology and Evolution of Cancer: From Discovery to Action.

Cancer progression is an evolutionary process. During this process, evolving cancer cell populations encounter restrictive ecological niches within the body, such as the primary tumor, circulatory system, and diverse metastatic sites. Efforts to prevent or delay cancer evolution-and progression-require a deep understanding of the underlying molecular evolutionary processes. Herein we discuss a suite of concepts and tools from evolutionary and ecological theory that can inform cancer biology in new and meaningful ways. We also highlight current challenges to applying these concepts, and propose ways in which incorporating these concepts could identify new therapeutic modes and vulnerabilities in cancer.
Authors
Somarelli, JA; Gardner, H; Cannataro, VL; Gunady, EF; Boddy, AM; Johnson, NA; Fisk, JN; Gaffney, SG; Chuang, JH; Li, S; Ciccarelli, FD; Panchenko, AR; Megquier, K; Kumar, S; Dornburg, A; DeGregori, J; Townsend, JP
MLA Citation
Somarelli, Jason A., et al. “Molecular Biology and Evolution of Cancer: From Discovery to Action.Mol Biol Evol, vol. 37, no. 2, Feb. 2020, pp. 320–26. Pubmed, doi:10.1093/molbev/msz242.
URI
https://scholars.duke.edu/individual/pub1416968
PMID
31642480
Source
pubmed
Published In
Molecular Biology and Evolution
Volume
37
Published Date
Start Page
320
End Page
326
DOI
10.1093/molbev/msz242

Improving Cancer Drug Discovery by Studying Cancer across the Tree of Life.

Despite a considerable expenditure of time and resources and significant advances in experimental models of disease, cancer research continues to suffer from extremely low success rates in translating preclinical discoveries into clinical practice. The continued failure of cancer drug development, particularly late in the course of human testing, not only impacts patient outcomes, but also drives up the cost for those therapies that do succeed. It is clear that a paradigm shift is necessary if improvements in this process are to occur. One promising direction for increasing translational success is comparative oncology-the study of cancer across species, often involving veterinary patients that develop naturally-occurring cancers. Comparative oncology leverages the power of cross-species analyses to understand the fundamental drivers of cancer protective mechanisms, as well as factors contributing to cancer initiation and progression. Clinical trials in veterinary patients with cancer provide an opportunity to evaluate novel therapeutics in a setting that recapitulates many of the key features of human cancers, including genomic aberrations that underly tumor development, response and resistance to treatment, and the presence of comorbidities that can affect outcomes. With a concerted effort from basic scientists, human physicians and veterinarians, comparative oncology has the potential to enhance the cost-effectiveness and efficiency of pipelines for cancer drug discovery and other cancer treatments.
Authors
Somarelli, JA; Boddy, AM; Gardner, HL; DeWitt, SB; Tuohy, J; Megquier, K; Sheth, MU; Hsu, SD; Thorne, JL; London, CA; Eward, WC
MLA Citation
Somarelli, Jason A., et al. “Improving Cancer Drug Discovery by Studying Cancer across the Tree of Life.Mol Biol Evol, vol. 37, no. 1, Jan. 2020, pp. 11–17. Pubmed, doi:10.1093/molbev/msz254.
URI
https://scholars.duke.edu/individual/pub1418086
PMID
31688937
Source
pubmed
Published In
Molecular Biology and Evolution
Volume
37
Published Date
Start Page
11
End Page
17
DOI
10.1093/molbev/msz254

From the Clinic to the Bench and Back Again in One Dog Year: How a Cross-Species Pipeline to Identify New Treatments for Sarcoma Illuminates the Path Forward in Precision Medicine.

Cancer drug discovery is an inefficient process, with more than 90% of newly-discovered therapies failing to gain regulatory approval. Patient-derived models of cancer offer a promising new approach to identify new treatments; however, for rare cancers, such as sarcomas, access to patient samples is limited, which precludes development of patient-derived models. To address the limited access to patient samples, we have turned to pet dogs with naturally-occurring sarcomas. Although sarcomas make up <1% of all human cancers, sarcomas represent 15% of cancers in dogs. Because dogs have similar immune systems, an accelerated pace of cancer progression, and a shared environment with humans, studying pet dogs with cancer is ideal for bridging gaps between mouse models and human cancers. Here, we present our cross-species personalized medicine pipeline to identify new therapies for sarcomas. We explore this process through the focused study of a pet dog, Teddy, who presented with six synchronous leiomyosarcomas. Using our pipeline we identified proteasome inhibitors as a potential therapy for Teddy. Teddy was treated with bortezomib and showed a varied response across tumors. Whole exome sequencing revealed substantial genetic heterogeneity across Teddy's recurrent tumors and metastases, suggesting that intra-patient heterogeneity and tumoral adaptation were responsible for the heterogeneous clinical response. Ubiquitin proteomics coupled with exome sequencing revealed multiple candidate driver mutations in proteins related to the proteasome pathway. Together, our results demonstrate how the comparative study of canine sarcomas offers important insights into the development of personalized medicine approaches that can lead to new treatments for sarcomas in both humans and canines.
Authors
Rao, SR; Somarelli, JA; Altunel, E; Selmic, LE; Byrum, M; Sheth, MU; Cheng, S; Ware, KE; Kim, SY; Prinz, JA; Devos, N; Corcoran, DL; Moseley, A; Soderblom, E; Hsu, SD; Eward, WC
URI
https://scholars.duke.edu/individual/pub1434058
PMID
32117764
Source
pubmed
Published In
Frontiers in Oncology
Volume
10
Published Date
Start Page
117
DOI
10.3389/fonc.2020.00117

Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer.

Circulating tumor cell (CTC) and cell-free (cf) DNA-based genomic alterations are increasingly being used for clinical decision-making in oncology. However, the concordance and discordance between paired CTC and cfDNA genomic profiles remain largely unknown. We performed comparative genomic hybridization (CGH) on CTCs and cfDNA, and low-pass whole genome sequencing (lpWGS) on cfDNA to characterize genomic alterations (CNA) and tumor content in two independent prospective studies of 93 men with mCRPC treated with enzalutamide/abiraterone, or radium-223. Comprehensive analysis of 69 patient CTCs and 72 cfDNA samples from 93 men with mCRPC, including 64 paired samples, identified common concordant gains in FOXA1, AR, and MYC, and losses in BRCA1, PTEN, and RB1 between CTCs and cfDNA. Concordant PTEN loss and discordant BRCA2 gain were associated with significantly worse outcomes in Epic AR-V7 negative men with mCRPC treated with abiraterone/enzalutamide. We identified and externally validated CTC-specific genomic alternations that were discordant in paired cfDNA, even in samples with high tumor content. These CTC/cfDNA-discordant regions included key genomic regulators of lineage plasticity, osteomimicry, and cellular differentiation, including MYCN gain in CTCs (31%) that was rarely detected in cfDNA. CTC MYCN gain was associated with poor clinical outcomes in AR-V7 negative men and small cell transformation. In conclusion, we demonstrated concordance of multiple genomic alterations across CTC and cfDNA platforms; however, some genomic alterations displayed substantial discordance between CTC DNA and cfDNA despite the use of identical copy number analysis methods, suggesting tumor heterogeneity and divergent evolution associated with poor clinical outcomes.
Authors
Gupta, S; Hovelson, DH; Kemeny, G; Halabi, S; Foo, W-C; Anand, M; Somarelli, JA; Tomlins, SA; Antonarakis, ES; Luo, J; Dittamore, RV; George, DJ; Rothwell, C; Nanus, DM; Armstrong, AJ; Gregory, SG
MLA Citation
Gupta, Santosh, et al. “Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer.Genes Chromosomes Cancer, vol. 59, no. 4, Apr. 2020, pp. 225–39. Pubmed, doi:10.1002/gcc.22824.
URI
https://scholars.duke.edu/individual/pub1421556
PMID
31705765
Source
pubmed
Published In
Genes Chromosomes Cancer
Volume
59
Published Date
Start Page
225
End Page
239
DOI
10.1002/gcc.22824

Molecular determinants for enzalutamide-induced transcription in prostate cancer.

Enzalutamide, a second-generation androgen receptor (AR) antagonist, has demonstrated clinical benefit in men with prostate cancer. However, it only provides a temporary response and modest increase in survival, indicating a rapid evolution of resistance. Previous studies suggest that enzalutamide may function as a partial transcriptional agonist, but the underlying mechanisms for enzalutamide-induced transcription remain poorly understood. Here, we show that enzalutamide stimulates expression of a novel subset of genes distinct from androgen-responsive genes. Treatment of prostate cancer cells with enzalutamide enhances recruitment of pioneer factor GATA2, AR, Mediator subunits MED1 and MED14, and RNA Pol II to regulatory elements of enzalutamide-responsive genes. Mechanistically, GATA2 globally directs enzalutamide-induced transcription by facilitating AR, Mediator and Pol II loading to enzalutamide-responsive gene loci. Importantly, the GATA2 inhibitor K7174 inhibits enzalutamide-induced transcription by decreasing binding of the GATA2/AR/Mediator/Pol II transcriptional complex, contributing to sensitization of prostate cancer cells to enzalutamide treatment. Our findings provide mechanistic insight into the future combination of GATA2 inhibitors and enzalutamide for improved AR-targeted therapy.
Authors
MLA Citation
Yuan, Fuwen, et al. “Molecular determinants for enzalutamide-induced transcription in prostate cancer.Nucleic Acids Res, vol. 47, no. 19, Nov. 2019, pp. 10104–14. Pubmed, doi:10.1093/nar/gkz790.
URI
https://scholars.duke.edu/individual/pub1409757
PMID
31501863
Source
pubmed
Published In
Nucleic Acids Res
Volume
47
Published Date
Start Page
10104
End Page
10114
DOI
10.1093/nar/gkz790