Sanjeevani Arora, PhD

Sanjeevani Arora, PhD
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This Fox Chase professor participates in the Undergraduate Summer Research Fellowship
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Assistant Professor

Lab Overview

My laboratory seeks to understand how innate differences (such as germline variants) in DNA replication and/or repair impact two critical areas in precision oncology: (1) what underlies an individual’s cancer risk, and (2) how an individual will respond to cancer treatment. Currently my work focuses on colorectal and renal tumors, but results from my work are applicable to multiple tumor types.

In the area of cancer risk prediction, we seek to identify and functionally assess novel or rare ‘risk’ germline variants in the population. Knowing which germline variants confer risk and which don’t is important because physicians don’t know how to act upon the massive number of variants of uncertain significance that have been identified by sequencing studies. We currently are evaluating variants in replicative DNA polymerases, POLE and POLD1, as these are known to cause mutagenesis, genetic instability and cancer (such as colorectal, endometrial).

Our approach to solving the ‘too many uncertain variants’ problem is based on a novel hypothesis, that germline POLE and POLD1 variants that are dysfunctional in the tumor also have a detectable dysfunctional signature in the germline. We are leveraging big data of tumor and germline to build a Germline Signature, which can be adopted into clinical practice to guide risk prediction and allow for application of cancer prevention strategies (e.g., lifestyle interventions) or early detection (e.g. by improving cancer screening panels). Collaborating with clinical partners, we plan to improve and validate this tool in prospective studies. Longer term, we plan to use the Germline Signature to build risk prediction models.

In the area of individual response to cancer treatment, we are integrating germline variation data with biological assessment of innate capacity to repair DNA damage to develop a ‘signature’ that predicts the magnitude of benefit from chemoradiation therapy. My approach is particularly novel because tumor-specific signatures have been sought but no biomarker has ever been established; this may be because prior studies did not evaluate innate factors. This work will deliver preclinical evidence that could allow for precision stratification of patients to therapies.

Currently, my two research directions are relatively separate. But I envision they will eventually meet. By pursuing both it may be possible to identify specific innate factors that influence both risk and response to treatment. Results may elucidate mechanisms common to many cancers and/or underlying predisposition to a certain tumor type.

  • DNA damage response and repair marker (gammaH2AX) significantly segregates early-onset colorectal cancer patients from matched cancer-free controls. GammaH2AX marker was assessed in peripheral blood lymphocytes of familial early-onset colorectal cancer patients and matched controls (Figure from Arora et. al., Gastroenterology 2015).

  • POLE and POLD1 are the major replicative DNA polymerases. Genetic mutations in POLE and POLD1 lead to proofreading errors occur throughout the genome, causing mutagenesis, genetic instability and cancer. The cancer spectrum of POLE and POLD1 includes colorectal, endometrial and other tumors. (Figure from Nicolas et. al., Gene 2016).

  • Early-onset renal cancer (eoRC) patients carry germline pathogenic variants in DNA damage response and repair genes These results indicate that patients diagnosed with eoRC may benefit from undergoing comprehensive multigene panel testing that includes genes outside of the scope of those currently known to increase renal cancer risk. (Figure from Hartman et. al., Scientific Reports 2020).

    Clinical

    Educational Background

    • Postdoctoral Fellow, Fox Chase Cancer Center, Philadelphia, PA, 2017
    • PhD, University of Toledo - Health Science Campus, Toledo, OH, 2012
    • MS, CMR Institute of Management Studies, Bangalore University, Bangalore, India, 2006
    • BS, Garden City College, Bangalore University, Bangalore, Karnataka, 2004

    Certifications

    • AACR Integrative Molecular Epidemiology: Bridging Cancer Biology and Precision Medicine, July 2017
    • ACMG Genomics Case Conference: "Solving the Unresolved: A systematic approach to WES Negative Patients in the Undiagnosed Diseases Network"

    Memberships

    • American Association for Cancer Research (AACR), Member
    • American Society for Cell Biology (ASCB), Member
    • American Society of Human Genetics (ASHG), Member
    • Association of Women in Science (AWIS), Member
    • European Association for Cancer Research (EACR), Member
    • Fox Chase Cancer Center, Co-Founder and Leader, "Women in Science" group
    • DNA Repair and Genome Stability working group (FCCC), Founder and organizer
    • Healthcare Businesswomen’s Association (HBA), Mentoring Program Director, “Represent Manager” -Women in Science
    • Journal of Biochemical Technology, Authors Advisory Board
    • World Association of Young Scientists, Member
    • 13th Annual Midwest DNA Repair Symposium, UT-HSC, Organizing Member and Host

    Honors & Awards

    • FY17 Peer Reviewed  Cancer Research Program (PRCRP) Career Development Award, 2018
    • NCI T32 training fellowship, 2016
    • Travel award for presenting at “ACMG Annual Clinical Genetics meeting” in Salt Lake City, UT, Fox Chase Cancer Center Postdoctoral program, 2015
    •  1st place- Oral presentation, 19th Annual Postdoctoral Day, Fox Chase Cancer Center, 2014
    •  "Board of Directors" Postdoctoral Fellowship, Fox Chase Cancer Center 2013

     

     

    Find the Fox Chase Cancer Center Trainee Association on LinkedIn

          Twitter: @sanjeevaniarora

     

     

     

     

     

     

    People

    • Philip Czyzewicz III, BS
      Scientific Technician II
      P2149

    Research Interests

    Cancer genetic studies to improve screening, early detection and treatment

    • Mechanisms underlying genetically undefined hereditary cancers
    • Predictive biomarkers for response to chemoradiation therapy
    • Novel strategies to screen for individuals at high-risk for cancer

    Lab Overview

    My laboratory seeks to understand how innate differences (such as germline variants) in DNA replication and/or repair impact two critical areas in precision oncology: (1) what underlies an individual’s cancer risk, and (2) how an individual will respond to cancer treatment. Currently my work focuses on colorectal and renal tumors, but results from my work are applicable to multiple tumor types. My long-term goal is to increase our understanding of DNA replication, and repair pathways and their role in colorectal and other cancers, to better predict cancer risk and reduce cancer incidence by allowing opportunities to implement cancer prevention strategies and early detection.

    Lab Description

    In the area of cancer risk prediction, we seek to identify and functionally assess novel or rare ‘risk’ germline variants in the population. Knowing which germline variants confer risk and which don’t is important because physicians don’t know how to act upon the massive number of variants of uncertain significance that have been identified by sequencing studies. We are evaluating genetic variants in replicative DNA polymerases, POLE and POLD1, as these are known to cause mutagenesis, genetic instability and cancer (such as colorectal, endometrial).

    Our approach to solving the ‘too many variants of uncertain significance’ problem is based on a novel hypothesis, that germline POLE and POLD1 variants that are dysfunctional in the tumor also have a detectable dysfunctional signature in the germline. We are leveraging big data of tumor and germline to build a Germline Signature, which can be adopted into clinical practice to guide risk prediction and allow for application of cancer prevention strategies (e.g., lifestyle interventions) or early detection (e.g. by improving cancer screening panels). Collaborating with clinical partners, we plan to improve and validate this tool in prospective studies. Longer term, we plan to use the Germline Signature to build risk prediction models.

    In the area of cancer treatment, we are investigating biomarkers of therapeutic response in rectal cancer. Neoadjuvant chemoradiation therapy (nCRT) is currently the standard treatment for locally advanced rectal cancer (clinical TNM stage II—III). Locally advanced rectal cancer accounts for ~60% of newly diagnosed patients. For many patients, nCRT has dramatically improved outcomes, but ~70-80% of patients who receive nCRT show poor or no response, and CRT is extremely toxic. Currently, there is no clinically actionable biomarker to predict which rectal cancer patients are likely to respond to nCRT. As a result, many patients are exposed to this toxic, DNA damaging therapy (radiation and chemotherapy) without benefit. Therefore, a biomarker for nCRT response would improve precision treatment, and ultimately improve survival and prevent recurrence in individual with rectal cancer.

    In the area of individual response to cancer treatment, we are integrating germline variation data with biological assessment of innate capacity to repair DNA damage to develop a ‘signature’ that predicts the magnitude of benefit from chemoradiation therapy. Our approach is particularly novel because tumor-specific signatures have been sought but no biomarker has ever been established; this may be because prior studies did not evaluate innate factors. This work will deliver preclinical evidence that could allow for precision stratification of patients to therapies.

    Currently, my two research directions are relatively separate. But I envision they will eventually meet. By pursuing both it may be possible to identify specific innate factors that influence both risk and response to treatment. Results may elucidate mechanisms common to many cancers and/or underlying predisposition to a certain tumor type.

    Misc

    Extramural Affiliations
     

    • Adjunct, Department of Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University
    • Adjunct, Department of Biochemistry & Molecular Biology, Drexel University School of Medicine

    Selected Publications

    Shah S.M., Demidova E.V., Lesh R.W., Hall M.J., Daly M.B., Meyer J.E., Edelman M.J., Arora S., Therapeutic implications of germline vulnerabilities in DNA repair for precision oncology. Cancer Treat Rev. 104: 102337, 2022. PMC9016579 https://www.ncbi.nlm.nih.gov/pubmed/35051883.

    Iqbal W., Demidova E.V., Serrao S., ValizadehAslani T., Rosen G., Arora S., Rrm2b is frequently amplified across multiple tumor types: Implications for DNA repair, cellular survival, and cancer therapy. Front Genet. 12: 628758, 2021.PMC8045241. https://www.ncbi.nlm.nih.gov/pubmed/33868369.

    Hartman TR, Demidova EV, Lesh RW, Hoang L, Richardson M, Forman A, Kessler L, Speare S, Golemis EA, Hall MJ, Daly MB, Arora S*. Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer. *Corresponding. Sci Rep. 2020 Aug 11;10(1):13518. doi: 10.1038/s41598-020-70449-5. PMID: 32782288

    Arora S*, Velichinskii R, Lesh RW, Usman A, Kubiak M, Bansal P, Edelman MJ, Borghaei H, and Boumber Y*. Existing and emerging biomarkers for immune checkpoint immunotherapy in solid tumors. *Co-corresponding. Adv Ther. 2019 Aug 13. doi: 10.1007/s12325-019-01051-z. [Epub ahead of print] Review. PMID: 31410780

    Nicolas E., Demidova E.V., Iqbal W., Serebriiskii I.G., Vlasenkova R., Ghatalia P., Zhou Y., Rainey K., Forman A.F., Dunbrack R.L., Jr., Golemis E.A., Hall M.J., Daly M.B., Arora S., Interaction of germline variants in a family with a history of early-onset clear cell renal cell carcinoma. Mol Genet Genomic Med. 7(3): e556, 2019. PMC6418363. 9.924

    Serebriiskii I.G., Connelly C., Frampton G., Newberg J., Cooke M., Miller V., Ali S., Ross J.S., Handorf E., Arora S., Lieu C., Golemis E.A., Meyer J.E., Comprehensive characterization of ras mutations in colon and rectal cancers in old and young patients. Nat Commun. 10(1): 3722, 2019. PMC6700103. 11.878

    Arora S., Heyza J.R., Chalfin E.C., Ruch R.J. ,Patrick S.M., Gap junction intercellular communication positively regulates cisplatin toxicity by inducing DNA damage through bystander signaling. Cancers (Basel). 10(10)2018. PMC6210410. 6.162

    Arora S., Huwe P.J., Sikder R., Shah M., Browne A.J., Lesh R., Nicolas E., Deshpande S., Hall M.J., Dunbrack R.L., Jr., Golemis E.A., Functional analysis of rare variants in mismatch repair proteins augments results from computation-based predictive methods. Cancer Biol Ther. 18(7): 519-533, 2017. PMC5639829. 2.879

    Nicolas E, Golemis EA, Arora S*. POLD1: Central mediator of DNA replication and repair, and implication in cancer and other pathologies. Gene 590:128-41, 2016. Pubmed PMID: 27320729 *corresponding.

    Nicolas E, Arora S, Zhou Y, Serebriiskii IG, Andrake MD, Handorf E, Bodia DL, Vockley JG, Dunbrack RL, Ross EA, Hall MJ, Golemis EA, Giri VN, and Daly MB.  Systematic evaluation of underlying defects in DNA repair as an approach to case-only assessment of familial prostate cancer. Oncotarget 6:39614-33, 2015, PubMed PMID: 26485759. PMCID: 4741850... Expand

    Additional Publications

    This Fox Chase professor participates in the Undergraduate Summer Research Fellowship
    Learn more about Research Volunteering.