2014 Annual Report. Caring for Carcinoid Foundation 20 Park Plaza, Suite 478 Boston, MA

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1 Caring for Carcinoid Foundation 20 Park Plaza, Suite 478 Boston, MA Annual Report The Caring for Carcinoid Foundation has established itself as the leading and most efficient not-for-profit funder of carcinoid, pancreatic neuroendocrine, and related neuroendocrine cancer research. CFCF has achieved this status through guidance from its Board of Directors, whose supports allows CFCF to operate efficiently, and its Board of Scientific Advisors, whose members provide a clear vision to funding research. Each year, CFCF organizes a state-of-the-science symposium to promote discussion and collaboration between neuroendocrine cancer clinicians and researchers. Since its inception, the Caring for Carcinoid Foundation (CFCF) has aggressively funded research in pursuit of cures and more effective treatments for carcinoid, pancreatic, and related neuroendocrine cancers. Since 2005, we have awarded more than $10 million in large-scale, multi-year research grants to leading scientists at renowned research institutions worldwide. Along with our focus on research, we are committed to supporting patients and their families. We conduct multiple Neuroendocrine Cancer Patient and Caregiver Educational Conferences annually; in 2014 we held educational events in Los Angeles and Philadelphia. Our award-winning and heavily trafficked website provides a searchable, neuroendocrine cancer-focused clinical trials finder, a doctor database, and a wide range of information about neuroendocrine cancers and available treatments. We publish an electronic newsletter steadily throughout the year, providing breaking news on research findings, treatments options, and other CFCF-specific updates AACR Awards Dinner (L-R) CFCF Director of Research, Lauren Erb, Dr. Herb Chen, and AACR Immediate Past President, Dr. Charles Sawyers Photos Credit: AACR/Todd Buchanan AACR Awards Dinner (L-R) CFCF Director of Research, Lauren Erb, Dr. Michael German, and AACR Immediate Past President, Dr. Charles Sawyers Photos Credit: AACR/Todd Buchanan 2014

2 Board of Directors Carol Branaman Chairman Stephen Kaufer Vice Chairman Jonathan Soroff Clerk Nicholas Vantzelfde Treasurer Stephen Blackwood Joseph Li, MD James Panagis, MD, MPH Board of Scientific Advisors The Board of Scientific Advisors provides scientific direction to the Caring for Carcinoid Foundation. All members of the Board of Scientific Advisors are: Pioneers in medical research Published authors in the top peer-reviewed medical journals Leaders of collaborative research projects at highly-ranked universities and institutes The Board of Scientific Advisors comprises highly distinguished medical leaders who share a commitment to discovering a cure for carcinoid cancer and related neuroendocrine cancers. George Fisher, M.D., Ph.D. Co-Chairman Associate Professor of Medicine, Stanford University Comprehensive Cancer Center Ramesh Shivdasani, M.D., Ph.D. Co-Chairman Associate Professor of Medicine, Harvard Medical School Gastrointestinal Cancer Center, Dana-Farber Cancer Institute Daniel Chung, M.D. Assistant Professor of Medicine, Harvard Medical School Clinical Director, Gastrointestinal Cancer Genetics Program, Massachusetts General Hospital Todd Golub, M.D. Associate Professor of Pediatrics, Harvard Medical School Founding Member and Director of the Cancer Program, Broad Institute Charles A. Dana Investigator of Human Cancer Genetics, Dana-Farber Cancer Institute Howard Hughes Medical Institute Investigator Dung Thi Le, M.D. Assistant Professor of Oncology, Johns Hopkins University

3 David H. Lee, Ph.D. Research Investigator Protein Analytics Abbott Bioresearch Center Andrew Leiter, M.D., Ph.D. Department of Medicine/Division of Gastroenterology, University of Massachusetts Medical School Professor of Medicine, University of Massachusetts Medical School Arnold Levine, Ph.D. Professor, The Simons Center for Systems Biology, Institute for Advanced Study Professor, Pediatrics and Biochemistry, Cancer Institute of New Jersey Thomas J. Lynch, M.D. Professor of Medicine and Director, Yale Cancer Center Physician-in-Chief, Smilow Cancer Hospital at Yale-New Haven Founding Member, Kenneth B. Schwartz Center Anil Rustgi, M.D. T. Grier Miller Professor of Medicine and Genetics, University of Pennsylvania Chief, Gastroenterology Division, University of Pennsylvania Director, Center for Molecular Studies in Digestive and Liver Disease, University of Pennsylvania Co-Director, Tumor Biology Program, Abramson Cancer Center William Sellers, M.D. VP and Global Head of Oncology, Novartis Institutes for Biomedical Research, Novartis Member, National Cancer Advisory Board Evan Vosburgh, M.D. Vice President, Verto Institute Executive Director, Raymond and Beverly Sackler Foundation Chairman, Medical Affiliates Board, Alliance for Cancer Gene Therapy Researcher and Clinician Panel at 2014 University of Pennsylvania Education Event

4 2014 Funded Research The Caring for Carcinoid Foundation is committed to funding the most promising research in order to discover cures and more effective treatments for carcinoid, pancreatic, and related neuroendocrine cancers. This year, we awarded over $1.5 million in research grants. We use a multidimensional approach of basic and translational research, and believe a disciplined, balanced approach has the greatest potential for discoveries, which could lead to better treatments and eventual cures for neuroendocrine cancers. Our research portfolio consists of projects designed to test new treatments, in the lab and in clinical trials. This is the most exciting period for the NET Research Foundation since its founding; doors are opening to new discoveries and new paths for possible treatments and cures. We are committed to: A structured, peer review process to ensure the highest quality research Partnerships with top scientists from the world s leading research institutions Recruiting the most promising researchers to study neuroendocrine tumors To date, we have awarded over $10 million in large-scale, multi-year research grants to leading scientists at renowned research institutions to fund neuroendocrine cancer research. We are currently funding research at 7 of the top 10 U.S. cancer centers. We are committed to collaboration and bringing researchers together to share information and progress that can accelerate better treatments and a potential cure. We are committed to opening the door to innovative approaches even wider through collaborations with other organizations. In 2014, the Caring for Carcinoid Foundation aimed to set research priorities to broaden and deepen its ever expanding research portfolio. The CFCF Board of Scientific advisors created a list of research priorities with a desire to launch high-impact research initiatives to achieve better diagnosis, better treatments, and better outcomes for neuroendocrine cancer patients NANETS Meeting University of Pennsylvania Patient Education Event (L-R) Board Member, Dr. Joseph Li, Dr. Edward Wolin, CFCF Executive Director, Ron Hollander, and Dr. David Metz Dr. Carl June speaks about the CFCF-UPenn Immunotherapy collaboration at 2014 University of Pennsylvania Patient Education Event

5 Research Priorities Creation of Multiple Cell Lines The foundation for all major cancer breakthroughs and the platform for early phase drug testing. The lack of validated cell lines is a crushing problem for the field. Most needed are multiple cell lines that reliably recapitulate the behavior of neuroendocrine cancers. Cell lines that successfully mimic cancer development and growth are important for many projects, like early phase drug testing. CFCF aims to raise funds for research awards and sponsor an innovative prize for the creation of the first reliable cell lines. Innovative Partnerships with Brain Cancer Organizations Pursuing breakthroughs with cancers that share neuroendocrine tumor characteristics. In 2011, CFCF-funded researchers were the first to uncover mutations in DAXX and ATRX among patients with neuroendocrine cancers. Since this landmark discovery, these mutations have been found in many cancer types including brain cancers. With the necessary support, CFCF would pursue partnerships with brain tumor foundations to co-fund work using brain tumor model systems to develop new therapeutic strategies. Beyond Genetics Epigenetics of carcinoid cancer, the new frontier in understanding tumor formation and growth. Mutations in epigenetic regulators among patients with pancreatic neuroendocrine tumors were uncovered in 2011 by CFCF funded researchers. It is believed that epigenetics may also be an underlying driver of carcinoid cancer growth. To date, a comprehensive analysis of the epigenetics of carcinoid cancer has not been conducted. CFCF will seek to raise the necessary funding to engage top labs in the field of epigenetics to study carcinoid cancer with the goal of discovering more molecular targets for therapies. Young Investigator Award Attracting the best and brightest to the community of researchers dedicated to control and conquer NETs. The lifeblood of any significant effort to conquer cancer is the ability to apply and replenish the best research brain power to the task. CFCF is committed to providing research support to promising young investigators; enabling them to pursue their research interests and reinforces their commitment to a career in NET research. AACR Partnership Attracting the most innovative clinical and basic researchers and laboratories to NET research. CFCF will be raising funds to, once again, renew its grant making partnership with the American Association for Cancer Research (AACR). This partnership allows us to draw upon the AACR s extensive and diverse membership to solicit proposals from a broad spectrum of cancer researchers. In the three years of this partnership, awarded projects have been some of the most innovative, translational studies in our portfolio. Safer, More Effective PRRT Clinical trial for Peptide Receptor Radiotherapy (PRRT). Peptide Receptor Radiotherapy (PRRT) is now widely used in Europe for the management of patients with neuroendocrine tumors and is in clinical development to determine safety and efficacy in the US. CFCF is considering funding a major US cancer center to conduct a small clinical trial of a new type of PRRT that showed promising results in a limited initial test in Europe. This trial aims to improve effectiveness while reducing side effects. If successful, it may open doors for approval of a whole new treatment option in the US.

6 Funded Research Projects Developing Novel Treatments for Neuroendocrine Tumors using CAR T-Cell Technology Carl June, MD; Xianxin Hua, MD, PhD; David Metz, MD - Abramson Cancer Center, University of Pennsylvania $400,000 (Duration: 2 years) Objective: To modify CAR T-cells to target and kill neuroendocrine tumor cells, a method that has had dramatic results in patients with other cancers. Success in this project could pave the way for trials of this breakthrough technology for neuroendocrine tumors. The Caring for Carcinoid Foundation is pleased to announce this grant, part of a multi-pronged strategy to harness the potential of the breakthrough field of immunotherapy to treat patients with neuroendocrine cancer. This project relies on the expertise of Carl June, MD, renowned for his work in immunotherapy. In particular, Dr. June s team spent many years developing CAR T serial killer T cells, which have been very successful in clinical trials treating patients with forms of leukemia and other cancers. This project brings together the multi-disciplinary team of Xianxin Hua, Carl June, and David Metz to develop CAR T cells to target receptors found on neuroendocrine tumor cells and then kill those cells. Research Objectives: 1. Generate and optimize somatostatin receptor specific CAR T cells that target the surface of human neuroendocrine tumors. 2. Test the anti-tumor activity of anti-sstr2 or SST-ligand CAR T cells in vitro. Abstract: There is a critical need to develop better treatments for patients with neuroendocrine tumors. A salient feature for many neuroendocrine tumors is the abnormally high level of somatostatin receptors on the surface of the tumor cells. Octreotide, a long acting analog of normal hormone somatostatin, and other similar derivatives have been long used to target somatostatin receptors on tumor cells to suppress the secretion of hormones from the tumor cells and growth of tumors. But Octreotide and its derivatives rarely kill tumor cells and reduce tumor mass. Tragically, 5-year survival for metastatic neuroendocrine tumors remains very low. Therefore, it is highly desirable to develop new and more effective therapies for patients with neuroendocrine tumors. Recently, adoptive T cell therapy involving engineered chimeric antigen receptors (CARs), which specifically target tumor associated antigens, has been reported to successfully eradicate human chronic lymphocytic leukemia and prevent its recurrence. These recent advances raise an exciting and real possibility that neuroendocrine tumor cells can be targeted and killed to improve the treatment of patients with neuroendocrine tumors. We will first develop CAR T cells designed to eradicate neuroendocrine tumors via targeting somatostatin receptors on the surface of the neuroendocrine tumor cells. Second, the best CAR T cells will be tested for their capability to specifically kill the cancer cells in cultured cells. These studies will aid the development of an entirely new and effective therapy for neuroendocrine tumor patients who have failed previous treatments.

7 Phase I/II Study of Intratumoral Ipilimumab with Anti-PD-L1 in Patients with Advanced, Progressive, Well-Differentiated Neuroendocrine Tumors Pamela Kunz, MD; Holbrook Kohrt, MD, PhD - Stanford University Cancer Center $600,000 (Duration: 2 years) Objective: To conduct a clinical trial for carcinoid and pancreatic neuroendocrine tumor patients, combining two immunotherapy drugs that are in clinical trials for other cancers. An innovative delivery technique will also be tested to reduce the risk of adverse effects. The Caring for Carcinoid Foundation is pleased to announce this grant, part of a multi-pronged strategy to harness the potential of the breakthrough field of immunotherapy to treat patients with neuroendocrine cancer. This project is a clinical trial combining two immune-therapies to treat both carcinoid and pancreatic neuroendocrine tumor patients. The trial involves not only combining two therapies, but also delivering one in a novel way with the potential to minimize what can be dangerous and prohibitive side effects. The investigators have requested substantial funding to conduct extensive immunologic testing, which will ensure that this clinical trial will be informative: both helping to identify potential biomarkers of immuneresponse and guiding future immune-based clinical trials. Click here to watch the video of Dr. Pamela Kunz explaining the Stanford Immunothearpy Clinical Trial, from the Stanford & Caring for Carcinoid Foundation's 4th AnnualNeuroendocrine Tumor Patient & Caregiver Educational Conference. Click here to access the Frequently Asked Questions about the Stanford Immunotherapy Clinical Trial. Research Objectives: 1. To determine the safety and feasibility of combining intratumoral anti-ctla4 treatment with anti-pd- L1 treatment in patients with well-differentiated, progressive, neuroendocrine tumors. 2. To assess efficacy endpoints of this regimen in neuroendocrine tumors. 3. To assess the immune pharmacodynamic correlates of this treatment. Abstract: The first approved immunotherapy for melanoma has already demonstrated striking clinical efficacy, with 1 in 10 patients experiencing long-term remissions. However, up to 1 in 2 patients develop significant toxicity. We hypothesize that an alternative route of administration of anti-ctla-4 therapy, via direct injection into a tumor site, will have the clinical potential to yield a systemic effect in combination with inhibition of the immune stop sign through anti-pd-l1 therapy. The goal of the Phase I/II clinical trial is to establish the proof-of-concept that we can further enhance the antitumor activity by being the first to demonstrate that intratumoral CTLA-4 therapy is safe, immunologically active, and therapeutically augments the systemic efficacy of intratumoral anti-ctla-4 injection in combination with anti-pd-l1 therapy in patients with well-differentiated, progressive, neuroendocrine tumors. Given that limited immunotherapeutics have been approved for tumors other than melanoma, this trial and the immune biomarkers identified have the capacity to be the first example. If successful, the proof-ofconcept demonstrated here will be applied to other cytotoxic and immunotherapeutics, thereby both reducing toxicity and maintaining efficacy, while also extending the clinical benefit and improved quality of life to cancer patients of any tumor histology type.

8 Multifunctional Nanomedicine for Targeted Carcinoid Cancer Therapy Herbert Chen, MD - University of Wisconsin-Madison $250,000 (Duration: 2 years) This grant was issued in partnership with the American Association for Cancer Research. Objective: To study a new anti-cancer drug with a new delivery method to target the somatostatin receptors present on neuroendocrine cancer cells. The investigators will conduct preclinical experiments to establish the feasibility of this new treatment strategy for treating patients with neuroendocrine, including carcinoid cancers. This research project brings together a multidisciplinary team to develop a new targeted treatment strategy for neuroendocrine cancer patients, including carcinoid cancer patients. This new treatment strategy combines a new anti-cancer drug with a new delivery method to target somatostatin receptors present on neuroendocrine cancer cells. The investigators will conduct preclinical experiments to establish the feasibility of this new treatment strategy for treating patients with neuroendocrine, including carcinoid, cancers. Research Objectives: 1. Investigate whether a new anti-cancer medication, TDP-A, optimally inhibits carcinoid cancer cell proliferation and bioactive hormone secretion in vitro. 2. Determine if tumor-targeted TDP-A loaded multifunctional drug nanocarriers can improve carcinoid tumor uptake and anticancer efficacy while decreasing systemic toxicity. Abstract: The incidence of carcinoid tumors has increased from 3% to 10% over the past 30 years. While surgical resection can be potentially curative, many patients develop metastatic disease precluding an operative cure. Moreover, patients with carcinoid metastases often develop malignant carcinoid syndrome with the associated endocrinopathies. This emphasizes the need for the development of new forms of therapy to prevent carcinoid cancer progression and to palliate hormone associated symptoms. This project combines the expertise of three professionals a chemical biologist who recently discovered a new and potent anticancer drug (ie, thailandepsin A [TDP-A]), a nanotechnologist/materials chemist who develops multifunctional drug nanocarriers for targeted cancer therapy, and a surgeon/neuroendocrine cancer biologist to develop multifunctional nanomedicines for targeted carcinoid cancer therapy. At the completion of the project, we intend to demonstrate that TDP-A is a potent anticancer drug for carcinoid cancers and that tumor-targeting TDP-A loaded nanocarriers have the potential to significantly enhance the efficacy of therapeutic treatments in carcinoid cancers while minimizing any undesirable side-effects.

9 Treating Neuroendocrine Tumors via Synthetic Lethality Michael German, MD - University of California San Francisco $250,000 (Duration: 2 years) This grant was issued in partnership with the American Association for Cancer Research. Objective: To test an FDA approved inhibitor of Mek1/2 (FDA approved for melanoma) in preclinical models of neuroendocrine tumors. This project is based on the concept of synthetic lethality. This concept originated in genetics where synthetic lethality occurs between two genes when mutation of either alone is compatible with life but mutation of both leads to death. Thus, targeting a synthetic lethal partner to a cancer relevant mutation kills cancer cells and spares normal cells. What makes this research unique and new is that previously, Dr. German s lab has identified a synthetic lethal gene partner for the MEN1 gene mutations commonly found in pancreatic neuroendocrine tumors. Dr. German believes that a synthetic lethal relationship exists between MEN1 loss and Mek1/2 inhibition. To study this hypothesis they will test an FDA approved inhibitor of Mek1/2 (approved for metastatic melanoma) in mouse models of pancreatic neuroendocrine tumors. The results will provide insight into the unique mechanisms that drive neuroendocrine cancer growth; and with positive results from the preclinical studies, use of an FDA approved drug may provide rapid translation to patients with neuroendocrine cancers including pancreatic neuroendocrine cancer and carcinoid cancer. Research Objectives: 1. Test the synthetic lethal interaction between Menin loss and Mek1/2 inhibition in preclinical models of pancreatic neuroendocrine tumors. 2. Analyze the interaction between MEN and RASSF1A in pancreatic neuroendocrine tumors. Abstract: Most of the genetic alterations relevant to neuroendocrine tumors are associated with tumor suppressors, most of which cannot be directly targeted since they are either not enzymes or simply not expressed. One possible solution to this problem could be to identify synthetic lethal interactions between these tumor suppressor mutations and proteins that can be targeted, or which already serve as targets of existing drugs. This concept originated in genetics where synthetic lethality occurs between two genes when mutation of either alone is compatible with viability but mutation of both leads to death. Thus, targeting a synthetic lethal partner to a cancer relevant mutation kills cancer cells and spares normal cells. Our laboratory has identified just such a synthetic lethal partner for the MEN1 gene mutations commonly found in pancreatic neuroendocrine tumors. While studying the specific pathways that control islet cell proliferation, we unexpectedly discovered that the classic oncogene K-Ras works differently in these cells to inhibit proliferation by activating the tumor suppressor RASSF1A, while Menin blocks the pro-proliferative B-raf/MEK/ERK arm of K-Ras signaling. These studies revealed a synthetic lethal interaction between Menin loss and Mek1/2 inhibition. We now propose to test the FDA approved inhibitor of Mek1/2 tramenitib in preclinical mouse and human models of pancreatic neuroendocrine tumors. We will also investigate the mechanisms underlying the unique growth suppressive action of K-Ras in neuroendocrine cell cancer by examining in cell lines and human PNET tumor samples the interaction between MEN1 and RASSF1A, which is frequently silenced in gut and pancreatic neuroendocrine tumors. The results should provide insight into the unique mechanisms that drive neuroendocrine cell cancer and help identify a synthetic lethal interaction for RASSF1A. Also, use of an FDA approved drug in preclinical animal studies may provide rapid translation to patients with carcinoid and pancreatic neuroendocrine tumors.

10 Patient Education Events The Caring for Carcinoid Foundation (CFCF) is dedicated to empowering patients and equipping them with a comprehensive understanding of treatment options so they can make the best informed decisions when deciding their care. In this spirit, CFCF is pleased to bring together our extensive community of patients, loved ones, medical professionals, and supporters for our annual series of free education events. Los Angeles Neuroendocrine Tumor Patient Education Conference CFCF returned to Southern California for its annual patient education event with Cedars-Sinai Medical Center. Date and Location: June 21 at Cedars-Sinai Medical Center, Los Angeles, CA Presenters Include: Edward Wolin, MD, Co-Director, Carcinoid & Neuroendocrine Tumor Program, Cedars- Sinai Medical Center Nicholas Nissen, MD, Director, Hepatobiliary and Pancreatic Surgery, Cedars-Sinai Medical Center Focus on Neuroendocrine Tumors: Patient and Caregiver Conference This is CFCF s third collaboration with the University of Pennsylvania Abramson Cancer Center. Those unable to attend in person will be able join a live discussion with conference presenters over the internet. Date and Location: Presenters Include: October 24 at the Hilton Hotel, Philadelphia, PA David Metz, MD, Associate Chief for Clinical Affairs, Gastroenterology, University of Pennsylvania 2014 Ride and Run for the Stripes 2014 Jimmy Fund Walk 2014 Los Angeles Patient Education Conference 2014 Pan Mass Challenge 2014 Anania Soul Cycle Event

11 Community Events The Caring for Carcinoid Foundation brings the neuroendocrine cancer community together through a series of highly visible athletic events and grassroots fundraising events across the nation. Team members and fundraisers include patients, caregivers, physicians and friends, run, bike, walk, and swim to a cure. The events benefit patients by empowering them to go out into their communities and advocate and fight for increased awareness of their disease. Cycle for Survival February 2014 Indoor cycling teams in New York and Boston Ride to raise funds for Dr. Diane Reidy Lagunes at Memorial Sloan Kettering Cancer Center 9th Annual S.C.O.P.E. 5K Run/Kids Fun Run/Walk March th Annual MD Anderson Scope 5K Run/Walk in Houston, Texas Team will be walking and running in memory of Jan Peine who passed away on January 31st Team Greg SoulCycle Ride for Caring for Carcinoid Foundation April 2014 Indoor cycling class at Soul Cycle on East 63rd Street in New York City. T 61 bikes to cycle and raise money to honor Gregory Anania 3rd Annual Walk with Chuck May 2014 Annual event since 2012 with 400 walkers 10 kilometer walk through Bergen County, NJ in memory of Charlie Eichholz Maple Point Middle School Dodgeball Tournament June 2014 Organized and sponsored by Maple Point Middle School in Middletown, Pennsylvania Event in honor of Dennis Howie, organized by wife Jennifer Howie, a teacher for gifted students Pan Mass Challenge August 2014 Long distance bike riding challenge across the state of Massachusetts Annual event for CFCF with 50+ Participants each year Remembering OC, Pay it Forward August 2014 Organized by Kristin O Connor, has in memory of husband Christian O'Connor Friends and family gather for a Mets game and barbeque Ride/Run for the Stripes August mile bike ride or a 5K run/walk for neuroendocrine cancer awareness Over 100 participants Dana Farber Jimmy Fund Walk September 2014 Annual event in Massachusetts with a team that continues to grow in numbers Biking for Debbie September 2014 Biking 82 miles from Ashton, MD to York, PA and back on the NCR and York Heritage Rail trails