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Principal Investigator: Amit Dutt, Ph.D

Contact details

Office Phone: +91-22-2740-5056

Laboratory Phone: +91-22-2740-5440/5445

 

Research Area

One Key Research Area:Integrated Cancer Genomics

Special interests: Characterization of Somatic Alterations in Human Cancer

About us:The overall aim of our laboratory is to understand the biological basis of various human cancers to guide development of clinical therapeutics.

Our efforts involve integrated characterization of somatic alterations of cancer-specimens by performing genome-wide analysis of copy number changes using SNP arrays, genomic re-sequencing using next generation sequencing platforms, and low throughput loss-of-function pooled RNAi mediated genetic screen using tumor derived cell lines (established in house). Our effort also focuses on experimental evaluation of functional relevance of somatic alterations identified by genomic approaches, using molecular and cellular approaches.

Projects

Projects: 

Defining the Cancer Genome of Head and Neck Squamous Cell Carcinoma (HNSCC) with SNP Arrays and Next Generation Sequencing Technology; Funding: Extramural – Wellcome Trust/ India Alliance: Rs. 3.5 Cr

The goal of this project is to identify activating mutations in head neck squamous cell carcinoma genomes that could represent therapeutic vulnerabilities. We will characterize large somatic copy number alteration (SCNA) and regions of loss of heterozygosity (LOH) in tumors and matched normals using Affymetrix 6.0 SNP array platform. The copy number information obtained will further be evaluated as quality criteria to infer stromal contamination and DNA integrity to allow selection of tumor samples harboring significant structural alterations. Significantly altered loci along with additional enzymatic-transferases and core components of signaling pathway will be sequenced using Next Generation Sequencing platforms.

Genome-wide RNAi screen with human pooled tyrosine kinase shRNA libraries in head and neck squamous cell carcinoma (HNSCC) cell lines ; Funding: Extramural - DBT RNAi Task Force. Rs. 96 Lakhs

The recent advances in genome scale technologies have revolutionized our understanding of the number and types of genetic alterations found in human tumors. While these studies are essential to our understanding of cancer, efforts to effectively convert this structural knowledge of the cancer genome into clinically useful therapeutics will require equally efficient methods to define the functional consequences of the alterations found by these comprehensive approaches. The goal of this project is discover vulnerabilities among multiple cell lines established in house at ACTREC from Indian tongue cancer patients. Pooled RNAi based screening offers a powerful methodology to identify causal genes according to the phenotypic changes of their inhibition. This approach uses a barcoded shRNA library pool to quantify the abundance of each shRNA followng infection and passage of cells through multiple generation to identify shRNA constructs that get depeleted from the pool targeting genes essenstial for the proliferation and survival of the cells.

Progestogenomics: Identify the transcriptional targets of progesterone in human breast cancer; Funding: Intramural. Rs. 69 Lakhs

Based on a recent randomized controlled clinical trial at Tata Memorial Center, pharmacological induction of a “progestogenic milieu” at the time of primary breast cancer surgery was found to be beneficial in terms of survival among node-positive patients, independent of their progesterone receptor (PR) status. While PR independent effect of progesterone has been shown to inhibit cell growth and invasiveness, cell detachment, and insulin-like growth factor receptor, the underlying mechanism whether progesterone exerts its biological effect through transcriptional targets of nuclear PR, or is mediated through the newly-defined family of membrane progesterone receptors (mPRs), through non genomic pathway or as a biochemical precursor to affect the levels of other hormone like estrogen and other molecules remains unclear. To test this notion, we will modulate the effect of progesterone in vitro in presence and absence of ER, multiple PR and HER-2 using human breast cancer cell lines with variant genotype harboring chromosomal deletion and then determine the global expression consequences of progesterone by microarray based expression analysis.

Profiling the incidence of novel alteration discovered in human lung cancer; Funding: – Intramural / Terry Fox Laboratories. Rs. 40.4 Lakhs (in process) Lung cancer remains a major unmet medical need in India and worldwide. About 63,000 new cases are diagnosed each year in India with deaths estimated at approximately 52,000, accounting for about 8% of all cancer deaths. Therapies targeting the EGFR and ALK tyrosine kinases have proven effective for lung adenocarcinoma patients whose tumors harbor genomic alterations of the EGFR and ALK genes, respectively. We recently reported 23% incidence of EGFR kinase domain mutations in 907 NSCLC patients with 74% response rate to oral tyrosine kinase inhibitor in Indian population (PLoS One. 2013 Apr 19;8(4):e61561). Identification of additional mutationally activated oncogenes beyond EGFR and ALK in lung cancer could result in novel therapeutic targets for this deadly disease. We are currently working on characterization of the most comprehensive spectrum of alterations in Indian lung adenocarcinoma patients from India.

Characterizing the somatic landscape of genetic alterations in human retroperitoneal liposarcomas; Funding: Intramural. Rs. 35 Lakhs

Retroperitoneal sarcomas are malignant tumours arising from mesenchymal cells in the anatomical space of the abdomen behind the peritoneum. They account for 15% of all soft tissue sarcomas. In patients with locally recurrent disease, the 3-year disease-specific survival in those patients who undergo a debulking surgery (surgery which involves removal of large portions of the tumour leaving behind some tumour attached to important blood vessels or vital organs), is no different from no surgery, at all. The lack of satisfactory treatment options using available conventional therapies (chemotherapy and radiation) has resulted in a world-wide interest in newer targeted therapeutic agents. However, effective development of targeted therapeutics that can interfere with the function of therapeutically relevant molecular targets remains unmet due to lack of our understanding of the molecular alterations that drive the tumorigenesis in these cancers. Here in this study, we are studying landscape of genetic alterations underlying the soft tissue sarcoma genome with potential to identify novel therapeutically relevant vulnerabilities.

Members

Laboratory Members:

Post Doctoral Fellows Jyoti Aich, Hemant Dhamne, Manoj Ramteke

Research Fellows Rohan Chaubal, Pratik Chandrani, Pawan Upadhyay, Prajish Sundaram Iyer, Mukul Godbole, Prachi Dhani, Vidya Sethunath, Ankita Singh, Reshma Patil, Mayur Tanna

Laboratory Assistant Deepak Ambule, Chetan Mhatre (shared)

Trial Coordinator Feroz Ullah Khan

System Administrator Vaibhav Kulkarni

Laboratory Manager Renu Dwivedi

Collaborators Dr. Indraneel Mittra, Dr. Sudhir Nair, Dr. Supriya Chopra (ACTREC); Dr. Kumar Prabhash, Dr. Sudeep Gupta, Dr. Rajendra Badwe (TMH); Dr. Randeep Singh (SAP Pvt Ltd)

Alumni

Prachi Terwadkar:

Dr. Kuldeep Patel: Currently Dr. Kuldeep Patel working as Manager (Biotechnology division) at Baroda Agro Chemicals Limited (BACL), India,

Sharan Janjuha: Pursuing Ph.D at The Max Delbrück Center for Molecular Medicine, Berlin, Germany

Deepak Iyer: Pursuing Ph.D at the Translational Research Laboratory, Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong

Rashmi Sharma: Pusuing Ph.D at Department of Biochemistry and Molecular biology, University of Debrecen, Hungary

Ratnam Prasad:

Kunal Karve: Pursuing Ph.D at the University of Calgary.

Maulik Vyas: Pursuing Ph.D in the Laboratory of Immunotherapy at the University of Cologne

Abhishek Thavamani: Pursuing Ph.D at the International Max Planck Research School, Tuebingen

Madhur Shetty: Pursuing Ph.D at the University of North Dakota, USA, at the Dept of Basic Sciences.

Ninad Oak: Pursuing Ph.D at the Molecular and Human Genetics Program at Baylor College of Medicine, Houston, USA Clinical Fellows

Prashant Jha: Fellow Biodesign, Stanford University, Stanford, CA

Karthik Chandra Vallam:

Snita sinukumar:

Opportunities: Dutt Lab considers application from deserving candidates round the year. Please write to the PI with an appropriate subject heading

Publications

2014

Upadhyay P, Dwivedi R, Dutt A Application of NGS in Cancer Research. Current Science, 2013. (In Press)

Mittra I, Khare NK…. Dutt A. Circulating nucleic acids damage DNA of healthy cells by integrating into their genome and induce oncogenic transformation. Under review.

Barreto SG, Dutt A*, Adarsh Chaudhary. A Genetic Model for Gallbladder Carcinogenesis and its Dissemination. Annals of Oncology 2014 * corresponding author

2013

Choughuke A, Prabhash K, Noronha V, Joshi A, Thavamani A, Chandrani P, Upadhyay P, Utture S, Desai S, Jambhekar N, Dutt A. Frequency of EGFR Mutations in 907 lung adenocarcioma Patients of Indian Ethnicity.. PLoS One. 2013 Oct 4;8(10):e76164.

Chougule A, Prabhash K, Noronha V, Joshi A, Thavamani A, Chandrani P, Upadhyay P, Utture S, Desai S, Jambhekar N, Dutt A. EGFR Mutation Subtypes and Geographical Distribution Among Indian NSCLC Patients. Indian J Cancer. 2013 Apr-Jun;50(2):107-11.

Noronha V, Prabhash K*, … Dutt A*, Mulherkar R. EGFR Mutations in Indian Lung Cancer Patients: Clinical Correlation and Outcome to EGFR Targeted Therapy. PLoS One. 2013 Apr 19;8(4):e61561 * co-corresponding author

Kumar R, Horvath A… Dutt A et al. The Global Cancer Genomics Consortium's Second Annual Symposium : Genomics Medicine in Cancer. Genes & Cancer 2013. DOI: 10.1177/1947601913484582

Pratik Chandrani and Amit Dutt Domain specific Targeting of Cancer. Chapter XII in Book entitled, "Nuclear Signaling Pathways and Targetting Transcription in Cancer", Springer Science & Business Media, 2013; 299-310

2012

Eswaran J, Gupta S, Dutt A, et al. The Global Cancer Genomics Consortium: Interfacing Genomics and Cancer Medicine. Cancer Res. 2012 May 24.

Cho J, .., Dutt A, et al Glioblastoma-derived EGFR carboxyl-terminal deletion mutants are transforming and are sensitive to EGFR-directed therapies. Cancer Res. 2011

2011

Dutt A* et al. Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer. PLoS One. 2011;6(6):e20351 * co-corresponding author

2010

Hammerman P, Sos ML, Ramos AH, Xu C, Dutt A et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discovery 2011.

Zhou W, Hur W, McDermott U, Dutt A et al. A Structure-guided Approach to Creating Covalent FGFR1 Inhibitors.Chem Biol. 2010 Mar 26;17(3):285-95

2009

Bass AJ, Watanabe H… Dutt A et al. SOX2 Is an Amplified Oncogene in Lung and Esophageal Squamous Cell Carcinoma. Nat Genet. 2009 Nov;41(11):1238-42.

Ramos AH*, Dutt A* et al. Amplification of chromosomal segment 4q12 in non-small cell lung cancer. Cancer Biol Ther. 2009 Nov;8(21):2042-50. * co first authors.

Dutt A, Salvesen H, Greulich H, Sellers WR, Beroukhim R, Meyerson M. Somatic mutations are present in all members of the AKT family in endometrial carcinoma. Br J Cancer ; 2009 Oct 6;101(7):1218-9

Salvesen HG, Cartel L, Mannelqvist M, Dutt A et al, Gene expression profiles identify an aggressive subtype of endometrial carcinoma associated with amplification and of PIK3CA. Proc Natl Acad Sci USA. 2009 Mar

2008

Ding L, Gedz Gad … Dutt A et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008 Oct 23;455(7216):1069-75.

Dutt A, et al.. Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8713-7.

2007

Thomas RK… Dutt A et al. High-throughput oncogene mutation profiling in human cancer. Nat Genet. 2007 Mar;39(3):347-51.

Dutt A, Beroukhim R. Single nucleotide polymorphism array analysis of cancer. sCurr Opin Oncol. 2007 Jan;19(1):43-9. Review.

Awards / Honors:

2011 Wellcome Trust/ DBT India Alliance Intermediate Fellowship

2010 Ramalingaswami Fellowship Award, Department of Biotechnology, Govt of India

2005 Awarded Swiss National Science Foundation Postdoctoral fellowship from the Govt of Switzerland, as an outstanding promising candidate.

2004 Awarded Julius Klaus Foundation Fellowship, University of Zürich, Switzerland.

2003 Awarded complete sponsorship by The Genetics Society of America, Bethesda and a Plenary talk

1997 NET (National Eligibility Test) for CSIR-UGC JRFship and Eligibility for Lectureship

1997 NET (National Eligibility Test) jointly conducted by ASRB and (ICAR) Dec.,1997.

1997 GATE (Graduate Aptitude Test Examination)

Affiliations:

American Associate of Cancer Research

Indian Association of Cancer Research

The Lung Cancer Consortium, Mumbai

Contact Us

Advanced Centre for Treatment, Research and Education in Cancer

Kharghar, Navi Mumbai - 410 210, india

Phone:+91-22-2740 5000

Fax: +91-22-2740 5085

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