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White Paper for India-UChicago Cancer Workshop:

Formation of a Strategic Partnership in Cancer Research between India and the University of Chicago

Sponsored by the University of Chicago Delhi Center and the National Institute of Biomedical Genomics (India) on March 23 and 24, 2015

Organizers:

Marsha R. Rosner Ben May Department for Cancer Research University of Chicago Comprehensive Cancer Research Center University of Chicago m-rosner@uchicago.edu

Partha P. Majumder National Institute of Biomedical Genomics Kalyani, India ppm1@nibmg.ac.in

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1. Background: The aim of this workshop, organized by Professor Marsha Rosner of the University of Chicago and Professor Partha Majumder, National Institute of Biomedical Genomics (NIBMG), India, was to initiate a conversation between researchers at the University of Chicago and at various Indian institutions geared towards undertaking joint research and capacity-building initiatives on cancer biology. Our ultimate goal is to leverage our respective strengths in the areas of genomics, signal transduction, big data analysis, and targeted therapies to undertake novel research that will not only have immediate application to cancer diagnosis, prognosis and therapeutic treatment, but will also serve as a model for addressing other diseases. 2. Attendees: University of Chicago Delhi Centre: Professor Gary Tubb, Director Department of Biotechnology, Govt. of India: Professor K. VijayRaghavan, Secretary; Dr. T.S. Rao, Senior Adviser; Mr. S. Sinha, Adviser; Dr. Bindu Dey, Adviser.

University of Chicago: There were 6 participants from the University of Chicago: Professor Eileen Dolan, Chair of the Committee on Phamacogenetics; Professor Geoffrey Greene, Chair of the Ben May Department for Cancer Research and co-Director, Ludwig Center for Metastasis; Professor Melody Swartz, Director of the Center for Immunobioengineering in the Institute for Molecular Engineering; Professor Kevin White, Director of the Institute for Genomics and Systems Biology, Professor Everett E. Vokes, John E. Ultmann Professor of Medicine and Radiation Oncology, Physician-in-Chief, University of Chicago Medicine and Biological Sciences and Chair, Department of Medicine, and Professor Marsha Rosner, former Chair of the Ben May Department for Cancer Research and founder of the Committee on Cancer Biology.

India: Dr. Mammen Chandy, Tata Medical Centre, Kolkata; Dr. Shubhada Chiplunkar, Advanced Centre for Treatment, Research and Education in Cancer, Mumbai; Dr. Kartiki Desai, National Institute of Biomedical Genomics, Kalyani; Professor Paturu Kondaiah, Indian Institute of Science, Bangalore; Dr. Sudhir Krishna, National Centre for Biological Sciences, Bangalore; Professor Tapas Kundu, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore; Dr. Arindam Maitra, National Institute of Biomedical Genomics, Kalyani; Professor Partha Majumder, National Institute of Biomedical Genomics, Kalyani; Dr. Mohandas Mallath, Tata Medical Centre, Kolkata; Dr. Geetashree Mukherjee, Tata Medical Centre, Kolkata; Professor Binay Panda, Genomics Applications and Informatics Technology Laboratories, Bangalore; Dr. Radhakrishna Pillai, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram; Dr. Susanta Roychoudhury, Indian Institute of Chemical Biology, Kolkata; Dr. Rajiv Sarin, Advanced Centre for Treatment, Research and Education in Cancer, Mumbai; Professor Sharmila Sengupta, National Institute of Biomedical Genomics, Kalyani; Professor Subrata Sinha, National Brain Research Centre, Manesar; Professor Kumar Somasundaram, Indian Institute of Science, Bangalore; Professor Parul Chakrabarti, Sir J.C.Bose Trust, Kolkata 3. Where We Stand Professor Gary Tubb and Professor K. VijayRaghavan welcomed this joint effort. Both affirmed their commitment to building relationships between the University of Chicago and Indian institutions engaged in cancer research. Professor VijayRaghavan stated that India has done well as a member of the International Cancer Genome Consortium (ICGC) and stated that the initial findings of the ICGC, not only from the Indian efforts but also from the efforts of other members, may be taken forward by embarking on in-depth research.

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He also stated that the Department of Biotechnology has a major commitment to cancer biology as additionally exemplified by the series of Provocative Questions workshops recently conducted in India by DBT, jointly with the National Cancer Institute in the United States. Both he and Professor Tubb strongly supported the workshop and added that they would support similar workshops in the future, as well. Here we list possible projects and collaborators from among the UChicago and India attendees but recognize that the specific projects and collaborators may change and expand.

Cancer Type There were two cancers that clearly were the foci of the majority of investigators attending the conference. Most of the attendees from India were focused on either breast or head and neck cancer, two of the most prevalent cancers in India, each of which served as the focus of a working group at the workshop. In addition, there is active research in India focused on cervical and brain cancer.

Research Area Two forefront and complementary approaches to cancer analysis and treatment were central themes at the workshop: Medical genomics and Cancer immunotherapy.

What is the opportunity? With the decreasing cost and increasing ease and speed of genomic sequencing, new drugs that target individual patients’ tumors are being identified for more personalized treatments. However, these new drugs have had disappointing impact in overall survival rates because most tumors mutate as the tumor progresses and evolves. Thus, no matter how effective a drug might be at killing most of the tumor cells, there will always exist some tumor cells that become resistant to the drug, only to later form new tumors with different properties. Treatment with a new drug can lead to a vicious cycle of patient relapse, each time resulting in more potent tumor cells and eventual mortality.

Immunotherapy is an exciting new avenue to treat cancer. It works by harnessing the patient’s own immune system to attack tumor cells. Immunotherapy holds huge promise in treating millions of patients whose cancers do not respond to current drug treatments. The past decade has seen remarkable growth in molecular and cellular immunotherapy to capitalize on this promise - from incredible research advances to innovative clinical application. Reflective of this excitement, cancer immunotherapy was named the 2013 “Breakthrough of the Year” by the leading scientific journal Science.

While immunotherapy works well for a subset of patients with certain cancers such as melanoma, multiple challenges need to be overcome before it can realize its full potential. Immunotherapy depends on both activating and recruiting host immune cells to kill the tumor, but tumors can evolve to evade these in a variety of ways. Therefore, new approaches are desperately needed before the immense potential of cancer immunotherapy can be realized clinically.

We propose that, by combining genomics-based targeted drug approaches with immunotherapy, we can overcome the limitations of each strategy alone. For example, certain drugs kill tumor cells in a way that stimulates the immune system. When these patients are also exposed to therapies that require an active immune system, then the drugs and the immunotherapy can act cooperatively to eliminate cancer in patients. With a focus on the immune system, it is possible to harness our evolving ability to design targeted drug therapy with activation of immune cells that specifically target cancer cells.

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However, major challenges remain in translating these promising approaches to a larger variety of cancer types, including those that are most difficult to treat with chemotherapy, such as triple-negative breast cancer. In addition to tumor heterogeneity, there are multiple mechanisms of drug and immune-resistance that arise to further promote tumor progression that we still do not completely understand. We have a long way to go in realizing the full potential of targeted drug treatment combined with cancer immunotherapy.

One major issue that restricts progress is the limited communication and collaboration between different research fields that contribute to cancer research – particularly those that arose from very different disciplines, such as tumor immunology, nanotechnology, computational genomics, imaging and tissue engineering. Here, we turn this model upside-down and propose a novel and innovative training program that will have broad and long-term impact by developing science teams to facilitate interdisciplinary training. Students from different fields, and in different countries, will work together towards a common goal, with the benefits of having more than one faculty mentor to shape their perspectives and enrich their experiences. The goals will be problem-based, while progress and integration will be facilitated by weekly videoconferenced team meetings and semi-annual retreats in alternating locations. 4. Why University of Chicago and India? The University of Chicago has a culture of innovation that is complemented by the focus on innovation in India (exemplified by the new genomics institute NIBMG) as a top priority of the next ten years. To date, India has lacked formal programs for research training of clinicians and has emphasized computational and engineering careers over those in the clinical science research. The University of Chicago has strong training programs and mentors in the biological and clinical sciences and unique computational resources including cloud-based cancer databases as well as new, highly innovative and world-class molecular engineering programs. By combining our respective strengths in biotechnology, computation and data analysis, as well as human resources, we have an unprecedented opportunity to establish an ongoing collaboration through interdisciplinary teams and make significant progress in this challenging disease. 5. What is the Opportunity? Harnessing our relative expertise to create novel approaches for genomics and cancer Immunotherapy We now have a unique opportunity to build teams between UChicago and India (coordinated by NIBMG) that bridge clinical oncology with cutting-edge research labs in genomics, cancer biology and immunology, immunoengineering and systems biology, focused on creating novel approaches to drug treatment and immunotherapy. Specifically, we will develop an innovative, interdisciplinary team-based research program focused on developing novel and integrative solutions to problems in cancer treatment. This research program will center around the interdependent goals of (1) providing interdisciplinary training to pre- or post-doctoral cancer researchers across India and at UChicago, and (2) building international teams that bridge different fields to address global challenges in cancer research and translation through innovative and collaborative approaches.

We will seed this effort by forming interdisciplinary and international teams of researchers between at least two laboratories with complementary expertise, one at UChicago and one at NIBMG or another Indian university/institute. These teams will initially focus on oral or breast cancers — two major cancers in both the US and India — and the genomic and immunological approaches that show promise to affect change in each. In addition, we will bring strength in computational/ statistical science to analyze the "big data" emerging

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from these studies, and bioengineering to design novel strategies to address any hurdles to creating effective immunotherapies.

Training Our initial goal is to support two pre- or post-doctoral trainees in Indian laboratories and two trainees in UChicago laboratories for each research project. In order to nurture expertise across teams, we will support the joint fellowship program by building out a suite of virtual and in-person opportunities for cross-training and mentorship, including:

Workshops in India, jointly conducted by UChicago and NIBMG, which will focus on cancer biology, cancer immunotherapy, and new technologies for cancer research. These workshops will be open to senior PhD students and junior faculty members from institutions across India and will serve as the basis for selection for exchange visits at UChicago.

Exchange visits will include opportunities for trainees from India to participate in short- and long-term research opportunities at UChicago; and for faculty/trainees from UChicago to train at an institution in India (primarily those with a focus on genomics/computational biology).

Skype and other video conferencing tools, including classes and seminars transmitted across UChicago and India, will maintain contact among team members.

Research

Although a modest endeavor compared to the enormous resources and efforts of major international cancer initiatives and centers, our proposal has great potential to substantially impact cancer outcomes by integrating and leveraging existing and complementary skills between UChicago and India. By bridging the two, we will be able to link the genetic, genomic, and proteomic data that will be collected and analyzed for tumors within the Indian population, with new advances, approaches, and tools being developed in real-time at UChicago and in India to make cancer therapies combining drug targets with immunotherapies more effective and more accessible for more patients.

In the first three years of our program, we will address the following challenges that currently limit the application of drug and immunotherapy to larger cohorts of patients in both the US and India, including:

Identifying predictive biomarkers and targets for personalized immunotherapy; Targeting host cells to modulate anti-tumor immunity and block metastatic progression; Developing accurate yet simple and low-cost means of detecting circulating tumor cells and tumor-

secreted vesicles from blood to monitor disease progression and guide therapy; and Developing physiologically relevant tissue-engineered models of patient tumors to enable rapid,

effective, and personalized real-time screening of potential therapies. 6. Next steps The India-UChicago Cancer Workshop on the Formation of a Strategic Partnership in Cancer Research between India and the University of Chicago held in March, 2015 was extremely successful. As summarized above, not only did the participants find common areas of interest, but they identified specific research questions and challenges in breast and oral cancer that would benefit from a partnership by teams from UChicago and India. Table 1 provides some details of possible teams of researchers for specific areas/cancer-types for engaging in continued dialogue with a view of proposing and submitting joint grant proposals to Indian and international funding agencies. It should be noted that the research of most participants cuts across the cancer types and research areas listed. Future collaboration between UC and India researchers will emphasize themes that

apply to multiple cancer types to enhance the impact of the research outcome.

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To maintain the momentum and move forward on this initiative, it is important that we convene a subsequent workshop that will be focused on Personalized Cancer Treatment based on innovative medical genomics and immunotherapy. Our plan is to run a more focused meeting that will delve more deeply into the science and form a basis for submission of funding proposals. To this end, we plan to submit an application for another workshop sponsored by the UChicago Delhi center within the next few months.

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Table 1. Details of Teams to Engage in Research Areas/Cancer Types

Names of Researchers Cancer-type/Research Area

University of Chicago India

(Wokshop Participants only)

Marsha Rosner Geoffrey Greene Melody Swartz Lev Becker Tom Gajewski

Paturu Kondaiah Kartiki Desai Geeta Mukherjee Shubhada Chiplunkar Rajiv Sarin Radhakrishna Pillai

Breast Cancer

Tumor heterogeneity

Tumor microenvironment

Immunengineering

Regulators of ER+ and ER- breast cancers

Kevin White Eileen Dolan Everett Vokes Ralph Weichselbaum

Partha Majumder Arindam Maitra Binay Panda Rajiv Sarin Tapas Kundu Susanta Roychoudhury

Head and Neck Cancer

Role of HPV and immune system

Pre-malignant lesion genomics

Role of inhibitors (such as Hat, Cox)

Diane Yamada Rimas Lukas Maciej Lesniak Yamini Bakhtiar Wendy Stock Michelle LeBeau

Sudhir Krishna Sharmila Sengupta Kumar Somasundaram Subrata Sinha

Mammen Chandy

Cervical Cancer

Immunomodulation in relation to HPV vaccination

Brain tumors

Genomics and proteomics

Inflammation and hypoxia Hematological Malignancies

Mary Ellen Geiger Ben Glick Melody Swartz Bob Grossman Andrey Rzhetsky Kevin White

Dibyendu Bhattacharyya Susanta Roychoudhury Binay Panda Partha Majumder Mohandas Mallath

Advanced Imaging Technologies

Exosomes and circulating tumor cells

3D Cultures

Bionimbus

High-throughput computing

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PHOTO GALLERY

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The Group

K. VijayRaghavan Marsha Rosner

Partha Majumder Geoffrey Greene

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Melody Schwartz Paturu Kondaiah

Radhakrishna Pillai Sharmila Sengupta

Partha Majumder, Shubha Chiplunkar, Subrata Sinha, Kevin White

Geeta Mukherjee, Sharmila Sengupta

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The Video Wall in the Lobby of the University of Chicago’s Delhi Center