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
Awarded By
FORMA Therapeutics, Inc.
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
Awarded By
Prostate Cancer Foundation
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
Awarded By
Arvinas Inc.
Role
Principal Investigator
Start Date
End Date

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

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

Publications:

Development of a precision medicine pipeline to identify personalized treatments for colorectal cancer.

BACKGROUND: Metastatic colorectal cancer (CRC) continues to be a major health problem, and current treatments are primarily for disease control and palliation of symptoms. In this study, we developed a precision medicine strategy to discover novel therapeutics for patients with CRC. METHODS: Six matched low-passage cell lines and patient-derived xenografts (PDX) were established from CRC patients undergoing resection of their cancer. High-throughput drug screens using a 119 FDA-approved oncology drug library were performed on these cell lines, which were then validated in vivo in matched PDXs. RNA-Seq analysis was then performed to identify predictors of response. RESULTS: Our study revealed marked differences in response to standard-of-care agents across patients and pinpointed druggable pathways to treat CRC. Among these pathways co-targeting of fibroblast growth factor receptor (FGFR), SRC, platelet derived growth factor receptor (PDGFR), or vascular endothelial growth factor receptor (VEGFR) signaling was found to be an effective strategy. Molecular analyses revealed potential predictors of response to these druggable pathways. CONCLUSIONS: Our data suggests that the use of matched low-passage cell lines and PDXs is a promising strategy to identify new therapies and pathways to treat metastatic CRC.
Authors
Altunel, E; Roghani, RS; Chen, K-Y; Kim, SY; McCall, S; Ware, KE; Shen, X; Somarelli, JA; Hsu, DS
MLA Citation
Altunel, Erdem, et al. “Development of a precision medicine pipeline to identify personalized treatments for colorectal cancer.Bmc Cancer, vol. 20, no. 1, June 2020, p. 592. Pubmed, doi:10.1186/s12885-020-07090-y.
URI
https://scholars.duke.edu/individual/pub1448846
PMID
32580713
Source
pubmed
Published In
Bmc Cancer
Volume
20
Published Date
Start Page
592
DOI
10.1186/s12885-020-07090-y

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

Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) Shows Efficacy Against Osteosarcoma.

Therapeutic advances for osteosarcoma have stagnated over the past several decades, leading to an unmet clinical need for patients. The purpose of this study was to develop a novel therapy for osteosarcoma by reformulating and validating niclosamide, an established anthelminthic agent, as a niclosamide stearate prodrug therapeutic (NSPT). We sought to improve the low and inefficient clinical bioavailability of oral dosing, especially for the relatively hydrophobic classes of anticancer drugs. Nanoparticles were fabricated by rapid solvent shifting and verified using dynamic light scattering and UV-vis spectrophotometry. NSPT efficacy was then studied in vitro for cell viability, cell proliferation, and intracellular signaling by Western blot analysis; ex vivo pulmonary metastatic assay model; and in vivo pharmacokinetic and lung mouse metastatic model of osteosarcoma. NSPT formulation stabilizes niclosamide stearate against hydrolysis and delays enzymolysis; increases circulation in vivo with t1/2 approximately 5 hours; reduces cell viability and cell proliferation in human and canine osteosarcoma cells in vitro at 0.2-2 μmol/L IC50; inhibits recognized growth pathways and induces apoptosis at 20 μmol/L; eliminates metastatic lesions in the ex vivo lung metastatic model; and when injected intravenously at 50 mg/kg weekly, it prevents metastatic spread in the lungs in a mouse model of osteosarcoma over 30 days. In conclusion, niclosamide was optimized for preclinical drug delivery as a unique prodrug nanoparticle injected intravenously at 50 mg/kg (1.9 mmol/L). This increased bioavailability of niclosamide in the blood stream prevented metastatic disease in the mouse. This chemotherapeutic strategy is now ready for canine trials, and if successful, will be targeted for human trials in patients with osteosarcoma.
Authors
Reddy, GB; Kerr, DL; Spasojevic, I; Tovmasyan, A; Hsu, DS; Brigman, BE; Somarelli, JA; Needham, D; Eward, WC
MLA Citation
Reddy, Gireesh B., et al. “Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) Shows Efficacy Against Osteosarcoma.Mol Cancer Ther, vol. 19, no. 7, July 2020, pp. 1448–61. Pubmed, doi:10.1158/1535-7163.MCT-19-0689.
URI
https://scholars.duke.edu/individual/pub1439712
PMID
32371588
Source
pubmed
Published In
Mol Cancer Ther
Volume
19
Published Date
Start Page
1448
End Page
1461
DOI
10.1158/1535-7163.MCT-19-0689