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Assistant Professor, Harvard Medical School

Location:
Newton, MA
Posted:
March 06, 2018

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Resume:

Pankaj Seth, PhD

** ******* ****, ****** ** US Citizen

617-***-**** ac4p1w@r.postjobfree.com

Summary

Seasoned researcher seeking to leverage extensive experience in translational oncology research. Proven capability to initiate and lead cross-functional collaborations/partnerships with key opinion leaders, academic leaders, and industry partners to identify and evaluate novel targets for the treatment of cancer. Immune Oncology experience: Identified novel surface markers on Myeloid Derived Suppressor Cells (MDSCs) and validated their therapeutic potential by using commercially available neutralizing antibodies for these novel targets in combination with immune checkpoint strategies in multiple syngeneic xenograft models. Evaluated role of acidosis in tumor microenvironment as it relates to immune suppression in context of modulating MDSCs and macrophage polarization. Target identification and validation: Mechanism of action studies with small molecule inhibitors using in vitro and ex vivo cellular assays. Evaluate therapeutic efficacy of small molecule inhibitors of metabolic enzymes in combination with immune checkpoint inhibition for modulating tumor microenvironment in syngeneic tumor models. Expertise in development and characterization of syngeneic and engineered mouse models of melanoma, lung cancer, and prostate cancer for target validation studies.

Biomarker Experience: Evaluated Biomarkers for monitoring antiangiogenic therapy and resistance in renal cancer patients. Evaluated Hyperpolarized Pyruvate Metabolic Imaging as a predictive and prognostic biomarker for prostate cancer using engineered mouse models.

Education

GEORGIA REGENTS UNIVERSITY (now AUGUSTA UNIVERSITY), Augusta, GA PhD, Biochemistry and Molecular Biology 1999

UNIVERSITY OF BOMBAY, Bombay, India

Master of Science in Biochemistry 1995

ST. XAVIER’S COLLEGE, Bombay, India

Bachelor of Science in Life Sciences 1993

Academic & Hospital Appointments

DEPARTMENT OF MEDICINE, HARVARD MEDICAL SCHOOL, Boston, MA DEPARTMENT OF INTERDISCIPLINARY MEDICINE, BETH ISRAEL DEACONESS MEDICAL CENTER Assistant Professor 2010 – Present

Instructor 2005 – 2010

Research Fellow 2002 – 2005

DANA-FARBER CANCER INSTITUTE, Boston, MA

DEPARTMENT OF ADULT ONCOLOGY

Research Fellow 1999 – 2002

Pankaj Seth, PhD Page 2-617-***-**** ac4p1w@r.postjobfree.com Professional Experience

DEPARTMENT OF MEDICINE, HARVARD MEDICAL SCHOOL, Boston, MA 2002 – Present DEPARTMENT OF INTERDISCIPLINARY MEDICINE, BETH ISRAEL DEACONESS MEDICAL CENTER Assistant Professor 2010 – Present

Leading an independent research laboratory investigating tumor immune microenvironment, specifically exploring deregulation of metabolic events in cancer and immune cells by utilizing variety of functional genomics and metabolomics approaches in cell-based as well as xenograft tumor models of lung, breast, prostate, and melanoma.

Investigated and validated novel markers of MDSCs in combination with IC inhibition strategies.

Investigated small molecule inhibitors of metabolic enzymes in combination with IC inhibition to alter tumor microenvironment in multiple tumor types.

Generated and characterized genetically engineered mouse model of non-small lung (oncogenic KRas, EGFR) and prostate cancer with inducible LDH-A deletion. Utilized models to demonstrate that reducing LDH-A levels in established tumors results in tumor regression and impacts cancer stem cells by altering their metabolic reprogramming in the tumor microenvironment.

Developed relationships and explored partnerships with key industry stakeholders.

Partnered with Bayer Pharma to assess the viability of targeting 6PGD and LDH-A to investigate potential therapeutic opportunities in metabolic reprogramming.

Collaborated with GSK to assess in vitro validation of small molecule inhibitors of LDH-A developed by GSK.

Maintained ongoing interdisciplinary collaborations across institutions on a wide variety of projects, including:

Investigated potential synergies of targeting metabolism in tumor microenvironment in combination with anti-PD1 treatment in transplantable tumor models of melanoma and colon cancer (with Drs. Vassilik Boussiotis and Gordon Freeman).

Evaluated effects of specific deletion in metabolic enzymes, including 6-phospho gluconate dehydrogenase (6PGD) and LDH-A in tumors, T cells and macrophages. Utilize generated mouse models to investigate role of metabolic reprogramming of tumor specific T cells and tumor-associated macrophages.

Investigate cross-talk between PI3Kinase inhibitors and altered metabolism of pentose phosphate pathway in triple negative breast tumors. Demonstrated that phosphoinositide 3-kinase regulates glycolysis through mobilization of aldolase (with Drs. Gerburg Wulf and Lewis Cantley).

Conducted in vivo metabolic imaging as a predictive biomarker for prostate cancer tumors using hyperpolarized pyruvate (with Dr. John Kurhanewicz at UCSF).

Labeled glucose carbon tracing for aberrant metabolic pathways in lung and prostate tumors (with Dr. Teresa Fan at University of Kentucky).

Investigated cancer metabolism targets, including ATP citrate lyase and malic enzyme 2 in studies investigating the mechanism of action of metabolic genes in modulating differentiation and epithelial-mesenchymal transition (EMT) and effect on tumor growth in xenograft models of non-small cell lung and breast cancer (collaborated and published with Drs. Lew Cantley and Vikas Sukhatme).

Evaluated the impact of fumarate hydratase on bioenergetics profile of VHL deficient renal cancer (collaborated and published with Dr. Marston Linehan at NCI).

Managed portfolio as principal investigator of NIH, DOD, and foundation grants.

Served as ad hoc reviewer for several peer-reviewed journals, including Cancer Research, Molecular Cell, PLOS, and Nature Communications.

Contributed as scientific advisor to Seahorse metabolic analyzer Core Facility, offering scientific help in data interpretation to determine mitochondria activity by measuring oxygen use and intracellular acidification. Instructor in Medicine 2005 – 2010

Senior Research Fellow 2002 – 2005

Characterized role of magic roundabout gene (Robo4) in endothelium and its impact on tumor angiogenesis.

Collaborated on roundabout guidance receptor 4 (Robo4), characterizing its role in a zebra fish model and further studying its interaction with ligand Slit 2 in retinal and choroidal vascular diseases.

Studied tumor metabolism in renal cancer using real time in vivo metabolic imaging with hyperpolarized pyruvate. Pankaj Seth, PhD Page 3-617-***-**** ac4p1w@r.postjobfree.com Professional Experience

Collaborated with fellow researchers on projects to validate oncology targets, including lipocalin2 (NGAL) and malic enzyme 2 (ME2).

Evaluated biomarkers for monitoring antiangiogenic therapy and resistance in renal cancer DANA-FARBER CANCER INSTITUTE, Boston, MA

DEPARTMENT OF ADULT ONCOLOGY

Postdoctoral Research Fellow 1999 – 2002

Identified and characterized novel genes via serial analysis of gene expression (SAGE) in mammary ductal carcinoma in situ (DCIS).

Characterized differentially regulated novel estrogen and tamoxifen-induced genes in breast cancer and normal breast epithelium. Partnered with PI to design novel adenoviral vectors to isolate estrogen and tamoxifen responsive cells analyzed by SAGE for differential expression of novel genes.

Collaborated and published on projects with other differentially regulated novel targets including lipocalin2 and high in normal-1 (HIN-1) identified in breast cancer SAGE analysis. MEDICAL COLLEGE OF GEORGIA (now AUGUSTA UNIVERSITY), Augusta, GA DEPARTMENT OF BIOCHEMISTRY

PhD Candidate 1995 – 1999

Cloned and characterized type 1 Sigma receptors and ligands.

Investigated expression pattern of the type 1 sigma receptor in the brain and identified critical anionic amino acid residues in the ligand-binding by site-directed mutagenesis.

Identified, cloned, and characterized organic cation transporters 2 / carnitine transporter (OCTN2) in epithelial cells. Grants

Title: Metabolic Reprogramming of Prostate Cancer and Antitumor Immunity by Targeting LDH A

(DoD Synergy Award) 2015 – 2018

Role: Principal Investigator

Goal: To investigate role of LDH A in immune cells utilizing novel mouse models. Title: Improving anti-tumor T cell immunity by targeting LDH-A functions: beyond the Warburg effect

(NIH, R01CA212605) 2017 – 2022

Role: Co-Investigator

Goal: To investigate impact on the differentiation program of tumor-specific T cells by targeting LDH-A. Title: Imaging of Therapies Targeted at the Warburg Effect in Lung Cancer

(NCI, 1 R01 CA169470-01A1) 2013 – 2018

Role: Co-Investigator

Goal: To characterize and maximize the acute metabolic effects by altering fermentative glycolysis and to determine the long-term effects of targeted metabolic therapy as investigated in tumor xenografts, and to assess the value of hyperpolarized NMR as a tool.

Title: Design, Synthesis, and Evaluation of Lactate Dehydrogenase Inhibitors (NCI, 1R01CA152330-01A1) 2012 – 2016 Role: Co-Investigator; Sub-Award Principal Investigator Goal: To develop novel inhibitors of the human enzyme lactate dehydrogenase A (LDH-A). Title: Pathway specific imaging in VHL deficient renal cancer (NCI, 1R01CA152330-01A1) 2011 – 2015 Role: Principal Investigator

Goal: To monitor changes in the flux of fermentative glycolysis non-invasively by hyperpolarize MRI. Pankaj Seth, PhD Page 4-617-***-**** ac4p1w@r.postjobfree.com Grants

Title: Targeting 6PGD in oncogenic KRas tumors (Bayer Pharma Grants4Targets Focus Award) 2014 – 2015 Role: Principal Investigator

Goal: To investigate inhibition of 6PGD in oncogenic K-Ras driven tumors. Title: Inhibition of fermentative glycolysis in KRas tumors (Bayer Pharma Grants4Targets Focus Award) 2012 – 2013 Role: Principal Investigator

Goal: To investigate inhibition of glycolysis in oncogenic K-Ras driven tumors. Title: Is LDH-A a viable target for prostate cancer therapy? (Defense Department Young Investigator Award) 2010 – 2013 Role: Principal Investigator

Goal: To investigate role of LDH-A in prostate cancer. Title: Magic Roundabout, a tumor endothelial marker (NCI K01, Howard Temin Award) 2005 – 2010 Role: Principal Investigator

Goal: To investigate role of magic roundabout (Robo4). Patents

Sukhatme VP, Karumanchi SA, Seth P, Hanai J, Mammoto T, Barasch J, Mori K. Lipocalin 2 for the Treatment, Prevention, and Management of Cancer Metastasis, Angiogenesis, and Fibrosis. US 200******** A1. Dec 10, 2009. Polyak K, Seth P, inventors. Dana-Farber Cancer Institute, Inc., assignee. Methods for identifying, isolating, and controlling the growth of estrogen-responsive cells. US 200******** A1. Mar 24, 2005. Polyak K, Seth P. Eit-6, a polypeptide encoded by an estrogen regulated gene. US 200******** A1. Dec 9, 2004. Publications

* indicates equal contributions

Seth P, Csizmadia E, Hedblom A, Vuerich M, Xie H, Li M, Serena LM, Wegiel B. Deletion of lactate dehydrogenase-A in myeloid cells triggers antitumor immunity. Cancer Res. 2017 Jul 1;77(13):3632-3643. (Equal Corresponding) Ren JG, Seth P, Huihui Y, Guo K, Hanai J, Husain Z, Sukhatme V. Citrate Suppresses Tumor Growth in Multiple Models through Inhibition of Glycolysis, the Tricarboxylic Acid Cycle and the IGF-1R Pathway. Sci Rep. 2017 Jul 3;7(1):4537.

Hu H, Juvekar A, Lyssiotis CA, Seth P, et al. Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton. Cell. 2016 Jan 28;164(3):433-46. Juvekar A, Hu H, Yadegarynia S, Seth P, et al. Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion. Proc Natl Acad Sci U S A. 2016 Jul 26;113(30). Patsoukis N, Chatterjee P, Sari D, Seth P, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nature Commun. 2015 Mar 26;6:6692. Xie H, Hanai J, Ren JG, Seth P. Targeting lactate dehydrogenase-A (LDH-A) inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor initiating cells. Cell Metab. 2014 May 6;19(5), 795-809. Pankaj Seth, PhD Page 5-617-***-**** ac4p1w@r.postjobfree.com Publications

* indicates equal contributions

Ren JG*, Seth P*, Clish C, et al. Knockdown of Malic Enzyme 2 Suppresses Lung Tumor Growth, Induces Differentiation and Impacts PI3K / AKT Signaling. Sci Rep. 2014 Jun 24;4:5414. Husain Z, Huang Y, Seth P., Sukhatme VP. Tumor-derived lactate modifies antitumor immune response: effect on myeloid- derived suppressor cells and NK cells. J Immunol. 2013 Aug 1;191(3):1486-95. Sun X, Han L, Seth P, et al. Disordered purinergic signaling and abnormal cellular metabolism are associated with development of liver cancer in Cd39/ENTPD1 null mice. Hepatology. 2013 Jan;57(1):205-16. Wegiel B, Gallo D, Csizmadia E, Seth P, et al. Carbon Monoxide Expedites Metabolic Exhaustion to Inhibit Tumor Growth. Cancer Res. 2013 Dec 1;73(23):7009-21.

Hanai J, Doro N, Seth P, Sukhatme VP. ATP citrate lyase knockdown impacts cancer stem cells in vitro. Cell Death Dis. 2013 Jun 27;4:e696.

Hanai JI, Doro N, Sasaki AT, Kobayashi S, Cantley LC, Seth P, Sukhatme VP. Inhibition of lung cancer growth: ATP citrate lyase knockdown and statin treatment leads to dual blockade of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT pathways. J Cell Physiol. 2012 Apr;227(4):1709-20. Seth P, Grant A, Tang J, et al. On-target inhibition of tumor fermentative glycolysis as visualized by hyperpolarized pyruvate, Neoplasia. 2011 Jan;13(1):60-71.

Ren JG*, Seth P*, Everett P, Clish CB, Sukhatme VP. Induction of Erythroid Differentiation in Human Erythroleukemia Cells by Depletion of Malic Enzyme 2. PLoS One. 2010 Sep 2;5(9). pii: e12520. Xie H, Vladimir A, Maria J, Seth P. LDH-A inhibition, a therapeutic strategy for treatment of Hereditary Leiomyomatosis and Renal Cell Cancer. Mol Cancer Ther. 2009 Mar;8(3):626-35. Wei F, Karihaloo A, Yu Z, Marlier A, Seth P, et al. Neutrophil gelatinase-associated lipocalin suppresses cyst growth by Pkd1 null cells in vitro and in vivo. Kidney Int. 2008 Nov;74(10):1310-8. Venkatesha S, Hanai J, Seth P, Karumanchi SA, Sukhatme VP. Lipocalin 2 antagonizes the proangiogenic action of ras in transformed cells. Mol Cancer Res. 2006 Nov;4(11):821-9. Seth P, Lin Y, Hanai J, et al. Magic Roundabout, Tumor Endothelial Marker: Expression and Signaling. Biochem Biophys Res Commun. 2005 Jul 1;332(2):533-4.

Bedell VM, Yeo SY, Park KW, Seth P, et al. Roundabout4 is essential for angiogenesis in vivo. Proc Natl Acad Sci U S A. 2005 May 3;102(18):6373-8.

Hanai J*, Mammato T*, Seth P*, et al. Lipocalin 2 diminishes invasiveness and metastasis of ras transformed cells. Lipocalin 2 diminishes invasiveness and metastasis of Ras-transformed cells. J Biol Chem. 2005 Apr 8;280(14):13641-7. Porter D, Weremowicz S, Chin K, Seth P, et al. A neural survival factor is a candidate oncogene in breast cancer. Proc Natl Acad Sci U S A. 2003 Sep 16;100 (19):10931-6.

Seth P, Porter D, Lahti-Domenici J, Geng Y, Richardson A, Polyak K. Cellular and molecular targets of estrogen in normal human breast tissue. Cancer Res. 2002 Aug 15;62(16):4540-4. Pankaj Seth, PhD Page 6-617-***-**** ac4p1w@r.postjobfree.com Publications

* indicates equal contributions

Seth P, Krop I, Porter D, Polyak K. Novel estrogen and tamoxifen induced genes identified by SAGE (Serial Analysis of Gene Expression). Oncogene. 2002 Jan 24;21(5):836-43.

Enerback C, Porter DA, Seth P, et al. Psoriasin expression in mammary epithelial cells in vitro and in vivo. Cancer Res. 2002 Jan 1;62(1):43-7.

Polyak K, Seth P. Phenol Sulfotransferases Join List of Low-Penetrance Breast Cancer Susceptibility Genes. Cancer Res Alert. 2001;2:137-140.

Seth P, Ganapathy ME, Conway SJ, Bridges CD, Smith SB, Casellas P, Ganapathy V. Expression pattern of the type 1 sigma receptor in the brain and identity of critical anionic amino acid residues in the ligand-binding domain of the receptor. Biochim Biophys Acta. 2001 Jul 25;1540(1):59-67. Krop IE, Sgroi D, Porter DA, Seth P, et al. HIN-1, a putative cytokine highly expressed in normal but not cancerous mammary epithelial cells. Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9796-801. Seth P, Wu X, Fei YJ, Huang W, Leibach FH, Ganapathy V. Mutations in novel organic cation transporter (OCTN2), an organic cation/carnitine transporter, with differential effects on the organic cation transport function and the carnitine transport function. J Biol Chem. 1999 Nov 19;274:33388-92. Wu X, Huang W, Prasad PD, Seth P, et al. Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation / carnitine transporter. J Pharmacol Exp Ther. 1999 Sep;290(3):1482-92. Tang NL, Ganapathy V, Wu X, Hui J, Seth P, et al. Mutations of OCTN2, an organic cation / carnitine transporter, lead to deficient cellular carnitine uptake in primary carnitine deficiency. Hum Mol Genet. 1999 Apr;8(4):655-60. Erratum in: Hum Mol Genet. 1999 May;8(5):943.

Ganapathy ME, Prasad PD, Huang W, Seth P, Leibach FH, Ganapathy V. Molecular and ligand-binding characterization of the sigma-receptor in the Jurkat human T lymphocyte cell line. J Pharmacol Exp Ther. 1999 Apr;289(1):251-60. Seth P, Fei YJ, Li HW, Huang W, Leibach FH, Ganapathy V. Cloning and functional characterization of a sigma receptor from rat brain. J Neurochem. 1998 Mar;70(3):922-31.

Seth P, Leibach FH, Ganapathy V. Cloning and structural analysis of the cDNA and the gene encoding the murine type 1 sigma receptor. Biochem Biophys Res Commun. 1997 Dec 18;241(2):535-40. Review Articles

Nikolaos P, Weaver JD, Strauss L, Herbel C, Seth P, Boussiotis VA Immunometabolic regulations mediated by coinhibitory receptors and their impact on T cell immune responses. Front Immunol. 2017 Apr. Herbel C, Patsoukis N, Bardhan K, Seth P, Weaver JD, Boussiotis VA. Clinical significance of T cell metabolic reprogramming in cancer. Clin Transl Med. 2016 Dec;5(1):29.

Nikolaos P, Kankana B, Weaver JD, Herbel C, Seth P, Lequn Li, Boussiotis VA. The role of metabolic reprogramming in T cell fate and function. Curr Trends Immunol. 2016;17:1-12. Bhatt RS, Seth P, Sukhatme VP. Biomarkers for monitoring antiangiogenic therapy. Clin Cancer Res. 2007 Jan 15;13(2 Pt 2):777s-780s.

Pankaj Seth, PhD Page 7-617-***-**** ac4p1w@r.postjobfree.com Invited Talks

Altering Fate and Function of cancer and T cells by targeting LDH-A 2017 Agios Pharma, Cambridge, MA

Targeting Immune metabolism 2017

Markey Cancer Center, Lexington, KY

Targeting Fermentative Glycolysis in Lung and Prostate Cancer 2014 Bayer Cancer Metabolism group, Bayer, Berlin, Germany Targeting Fermentative Glycolysis in Lung and Prostate Cancer 2014 Translational advances in cancer cell signaling and metabolism, EMBO workshop, Bilbao, Spain Modulating LDH-A Results in Therapeutic Efficacy in Highly Glycolytic Tumors 2013 3rd Annual MMHCC Co-Clinical Trials Workshop, Boston, MA LDH-A, therapeutic target in Kidney Cancer 2012

Kidney Cancer Association and NCI Kidney Cancer SPORE, Chicago, IL Targeting Fermentative Glycolysis for therapeutics 2011 GSK Cancer Metabolism Group, GSK, Philadelphia, PA Awards

Dvorak Young Investigator Award 2016 – 2017

Dana-Farber / Harvard Cancer Center Kidney Cancer SPORE Award 2009 – 2010 Dana-Farber / Harvard Cancer Center Kidney Cancer SPORE Award 2005 – 2007 Department of Defense Breast Cancer Research Fellowship 1999 – 2002 Excellence in Research Award for Graduate Student 1998 – 1999 Graduate Research Fellowship from Medical College of Georgia 1996 – 1999



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