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Last Updated: 09/10/21

Johns Hopkins SPORE in Gastrointestinal Cancer

Johns Hopkins School of Medicine

Principal Investigator(s):

Alison Klein, PhD
Alison Klein, PhD

Principal Investigator(s) Contact Information

Alison Klein, PhD
Professor of Oncology, Pathology and Medicine
Professor of Epidemiology
Co-Leader Cancer Prevention and Control
Johns Hopkins School of Medicine
1550 Orleans Street, CRBII 354
Baltimore, MD 21231
(410) 955-3502

Overview

This application for continuation of the Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancer at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins supports a highly interactive, multidisciplinary program. Four research projects, four cores, a career development and a research developmental program are proposed to extend our translational research in colorectal and pancreatic cancer.

Project 1, Improving Pancreatic Cancer Risk Assessment: Clinical/Population Leader Dr. Alison Klein and Basic Co-Leader Dr. Michael Goggins.

Project 2, Neo-antigen Vaccines for Pancreatic Cancer and Colorectal Cancer. Basic Co-Leaders Dr. Elizabeth Jaffee and Clinical Leader Dr. Nilo Azad.

Project 3, Diagnosis and Management of Pancreatic Cysts: Clinical Leader Dr. Anne Marie Lennon and Basic Co-Leaders Drs. Ken Kinzler and Bert Vogelstein

Project 4, Using TME genetics and immunobiology to drive combination immunotherapies. Basic Co-Leader Dr. Elizabeth Jaffee and Clinical Leaders: Drs. Dung Le and Lei Zheng

The cores support the research programs (Admin Core: Administration and Communication, Dr. Alison Klein; Core 1, Statistics/Bioinformatics, Dr. Robert Scharpf: Core 2, Human Tissue Research and Logistics, Dr. Elizabeth Thompson; Core 3, Familial and Population Cancer Registries, Drs. Frank Giardiello and Alison Klein.

The Career Development Program (Dr. Scott Kern) aids the emergence of new investigators and the Research Developmental Program (Dr. Bert Vogelstein) provides rapid funding of innovative directions

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Project 1: Improving pancreatic cancer risk assessment

Project Co-Leaders:
Alison Klein, MHS, PhD (Clinical/Population Co-Leader)
Michael Goggins, MD (Basic Science Co-Leader)

Our overall foundation is that there are identifiable genetic predispositions to the development of pancreatic cancer. Our prior work has established the importance of inherited factors in the development of pancreatic cancer, and identified BRCA2, PALB2 and ATM as familial pancreatic cancer genes. However, the familial clustering is still unexplained for 80% of pancreatic cancer families. This leads to our overall translational goals; to increase our scientific evidence base to inform genetic counseling and risk assessment of at-risk individuals by identifying new pancreatic cancer genes and to identify people at high-risk who would benefit most from future chemoprevention trials and efforts to screen for early, and therefore potentially curable, pancreatic neoplasia. As part of this project we will 1A) To determine the contribution of germline structural variants to pancreatic cancer susceptibility; 1B) To identify novel pancreatic cancer susceptibility genes through a combined analysis of single nucleotide variants and structural variants: 2) To evaluate and characterize candidate pancreatic cancer susceptibility genes; 3A) To determine if personal or family histories of cancers other than pancreatic cancer can be used to better estimate the risk of developing pancreatic cancer 3B) to develop and validate an enhanced and clinically practical pancreatic cancer risk stratification model incorporating risk factors identified in Aims 1, 2 and 3A.

In summary, through this project we hope to continue to unravel the genetic basis of inherited pancreatic cancer and develop practical, robust and clinically relevant tools to guide precision risk-management strategies for these families.

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Project 2: Neo-antigen vaccines for pancreatic cancer and colorectal cancer

Project Co-Leaders:
Nilo Azad, MD (Clinical Science Co-Leader)
Elizabeth Jaffee, MD (Basic Science Co-Leader)

Immune checkpoint inhibitors (ICIs) are providing durable clinical responses in about 20% of cancer patients. But these agents have minimal effect in cancers without intratumoral T cells. Approaches that turn currently unresponsive cancers into ones that are more “antigenic” are needed to sensitize tumors to ICIs. Emerging data suggest that it should be possible to develop approaches that combine a neo-antigen targeting vaccine to activate and expand the limited repertoire of T cells specific for the expressed neo-antigens found in low mutation cancers such at PDAC and MSS CRC, with ICIs to induce clinically relevant anti-tumor responses. But challenges to successful immunization include knowledge about the repertoire and functional state of pre-existing anti-tumor T cells, identification of the best neoantigens and vaccine adjuvants, and approaches that more precisely predict which expressed neo-antigens are the best T cell targets for immunization. In addition, rare subsets of pancreatic cancer such as adenosquamous (ASQ) pancreatic cancer may have different biological features compared to the more common pancreatic adenocarcinoma. These differences in ASQ pancreatic cancer have been studied by Hopkins investigators and demonstrated that, unlike PDA, ASQ cancers have a dynamic TME with an abundance of TILs in subsets of tumors. TILs in the TME have correlated with response to ICI therapy in multiple histologies, and these data ICI therapeutic strategy may be beneficial for ASQ patients. We thus hypothesize that ICI therapy with an anti-PD1 agent will be effective in patients with ASQ pancreatic cancer. We further hypothesize that neoantigens are attractive vaccine targets that can raise T cells to be available for further activation by ICIs in typical PDA and MSS CRC. Aim 1: we will test ICI in ASQ pancreatic cancer patients. Aim 2: we will evaluate the role of MHC Class II neoantigens in our preclinical pancreas cancer model in an effort to improve our current neoantigen-targeting vaccine strategy. Aim 3: we will evaluate neo-antigen targeted combination immunotherapy in MSS CRC and PDA patients.

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Project 3: Diagnosis and management of pancreatic cysts

Project Co-Leaders:
Anne Marie Lennon, MD (Clinical Science Co-Leader)
Ken Kinzler, PhD (Basic Science Co-Leader)
Bert Vogelstein, MD (Basic Science Co-Leader)

Over one million individuals are identified with pancreatic cysts every year. IPMNs and MCNs, are pre-cursors to pancreatic cancer, and offer the opportunity for the early detection, or even prevention, of pancreatic cancer. In contrast, serous cystadenomas or pseudocysts, are benign. Currently tools are inadequate to fully delineate these lesions prior to surgical resection, with up to 68% of the operations performed on patients with a pancreatic cyst ultimately found to be unnecessary. Guidelines recommend lifelong surveillance for IPMNs, however this is based on the lowest level of scientific evidence. Furthermore, no data exists on the molecular progression of IPMNs and MCNs in situ. We developed a Comprehensive Cyst (CompCyst) EUS companion test which combines clinical, radiological, genetic and protein marker data. In an initial evaluation of 862 surgically resected pancreatic cysts, the CompCyst test had a superior performance for identifying cysts which required surgery, needed surveillance, or were benign, compared with the current routine evaluation. The Aims of the proposed project are to: Aim 1: Evaluate the genetic and clinical natural history of pancreatic cysts in a prospective international study. Aim 2: Evaluation and optimization of approaches for the management of pancreatic cysts. Aim 3: Develop a Second-Generation CompCyst test (CompCyst2).

The overarching goal of Project 3 is to develop a clinically relevant tool which will be incorporated into clinical practice and will improve outcomes for patients with pancreatic cysts, specifically avoiding unnecessary surveillance or surgical resection.

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Project 4: Using TME genetics and immunobiology to drive combination immunotherapies

Project Co-leaders:
Elizabeth Jaffee, MD (Basic Science Co-Leader)
Dung Le, MD (Clinical Science Co-Leader)
Lei Zheng, MD (Clinical Science Co-Leader)

Immunotherapy has become a game changer for about 20% of patients with metastatic cancers who until now would die quickly of their disease. This new class of immunotherapies induce durable responses that can last for years without further therapy. These agents (immune checkpoint inhibitors) act on T cells that are inactivated due to immune checkpoint signals that inhibit their infiltration into and function within tumors. But for about 80% of patients, immunotherapy has not been effective, and immune unresponsiveness is likely the result of failure to activate effector T cells together with the existence of multiple suppressive signals rather than a predominant immune checkpoint signal within resistant tumors. Accumulating data suggests that it is possible to convert non-immunogenic tumors into one that respond to immunotherapy. Thus, this proposal will address the next big question in cancer immunotherapy: why do some cancers respond to checkpoint immunotherapy and exhibit durable responses, while others either develop resistance (adaptive resistance) or are naturally resistant. Understanding primary and adaptive resistance mechanisms will translate into effective scientifically driven combination immunotherapies that combat resistance.

Our group has led the development of both single agent and combination therapy for pancreatic adenocarcionoma (PDA) and colorectal carcinoma (CRC) and have recently received FDA approval for Pembrolizumab for the treatment of patients with microsatellite instability (MSI) high tumors. In addition, we have shown that treatment of patients with a vaccine can induce cancer specific T cells that infiltrate into PDA and CRC tumors, opening the door for novel combination immunotherapies. In this proposal, we will use specimens already collected and prospectively being collected on trials that are demonstrating both sensitivity and primary and adaptive resistance to immunotherapies, to define additional signals required to convert insensitive tumors into ones that respond to immunotherapy. A number of potential candidates of immune signatures for response/resistance have been identified by a multi-omic approaches and are now being further validated through this SPORE project.

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Administration Core

Core Director:
Alison Klein, MHS, PhD

The primary function of the Administrative Core is to provide for the overall organizational, administrative and scientific management of the GI SPORE Program.

This will be accomplished by the following aims:

  1. Provide the organizational structure to efficiently enable all SPORE activities.
  2. Provide the administrative foundation for the management of SPORE activities, including research projects, shared resources Cores, developmental research projects, career enhancement programs and supplemental actives.
  3. Provide overall scientific management for the GI SPORE program.

This Core will be responsible for managing the SPORE and disseminating information within the SPORE. The Core will also manage external interactions. The Core is designed for low-cost, yet efficient administration and communication in order to focus funds on research activities.

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Statistics/Bioinformatics Core

Core Director:
Robert Scharpf, PhD

The goal of the GastroIntestinal Biostatistics and Bioinformatics Core (GI-BBC) is to provide wide-ranging, high-quality statistical and bioinformatics support to the GI SPORE. The primary aim of the GI-BBC is to assist GI SPORE investigators in the design, conduct and analysis of laboratory and clinical studies proposed in this SPORE application. The GI-BBC will focus its efforts on assisting both the clinical and laboratory investigators in translating their pre-clinic studies into clinical studies by providing state- of-the-art experimental designs and analyses through statistical consultation and in collaboration with respect to methodology, feasibility, analysis, and reporting of clinical and laboratory studies. In addition, the GI-BBC will serve as an ongoing resource for all GI-SPORE investigators.

Centralization of statistical needs within the GI-BBC core will provide SPORE investigators with open access to a team of statisticians with the skill set necessary to meet the current and future goals of the SPORE in a cost-effective manner. In addition, it will facilitate communication across SPORE projects, aiding the translation of research findings into the clinial setting.

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Human Tissue Research and Logistics Core

Core Director:
Elizabeth Thompson, MD, PhD

The purpose of this shared resource is to provide human tissues, biological fluids, and expert pathologic interpretation for investigators in all SPORE investigators. The biospecimens are harvested and banked in accordance with the National Cancer Institute’s Best Practice Guidelines for Biorepositories. Distribution of these specimens to SPORE investigators has resulted in over 120 publications in the past 5 years. This Core procures additional xenografts, fresh frozen colorectal and pancreatic neoplasms and blood and pancreatic juice samples, and provides expert pathologic consultation to investigators. Specimens are collected under the supervision of pathologists with expertise in colorectal and pancreatic neoplasia in close collaboration with clinical specialists in these areas and in similarly close collaboration with basic research investigators to maximize translational impact of the projects. The Core is also involved in the development of technologies that augment and expand the range and depth of research projects undertaken by SPORE investigators. These technologies help maximize the translational impact of banked specimens. Current technologies in use and under development include multi-spectral immunofluorescence and various approaches to three-dimensional tissue imaging.

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Familial and Population Cancer Registries Core

Core Directors:
Alison Klein, MHS, PhD
Frank Giardiello, MD

The genesis of colorectal and pancreatic cancer involves the interaction of environmental and heritable causes. Key to discoveries in diagnosis and treatment of these malignancies is the understanding of these factors by investigation of well-characterized and available patient data and specimens.

The goal of Core 3 is to provide SPORE and other investigators with these materials to support the research of familial, environmental and molecular genetic factors in both colorectal and pancreatic cancer. This Core includes: 1) families with a history of familial aggregation of colorectal cancer, early onset colorectal cancer and polyposis syndromes and 2) family histories and food frequency questionnaires on patients evaluated for colorectal neoplasm 3) families with a history of pancreatic cancer 4) patients with cystic neoplasms of the pancreas and 5) control individuals.

The specific aims of our Family and Population Core are:

The importance of the knowledge gained by the data accumulated by this Core is significant and multifactorial. Benefits from this knowledge include risk markers necessary for the initiation of preventative surveillance strategies, diagnostic markers essential to the appropriate medical and surgical treatment of these tumors, and therapeutic targets needed for the development of medical therapies.

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Developmental Research Program

Program Director:
Bert Vogelstein, MD

The Developmental Research Program of our GI SPORE is designed to provide initiating funds for novel explorations related to GI cancer and integrate the awardee into the SPORE community. The Program continues to be a major focus of the SPORE because it provides for a continuous flow of innovative ideas and activity to stimulate investigation in the context of SPORE translational research. The Developmental Research Program provides a means to respond to new opportunities, and is designed to encourage and facilitate new research efforts. The Program takes advantage of the broad expertise of researchers at The Johns Hopkins University and of external investigators by providing funds for pilot projects with potential for development into full-fledged translational research avenues, collaborations, and new methodologies for integration into other Research Projects.

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Career Enhancement Program

Program Director:
Scott Kern, MD

The goal of this proposed program is to provide funds for career development of faculty members who are or will be specifically involved in translational research in gastrointestinal cancer. Eligible candidates include faculty members at any level in the University who wish to direct their efforts into translational research in gastrointestinal cancer. One Career Enhancement awardee will be selected each year. We anticipate providing multiple years of support to each awardee. Support for the “out years”, those beyond the maximum supported time permitted by SPORE guidelines, is provided by institutional funds dedicated to the GI SPORE.

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Institutional SPORE Website

https://www.hopkinsmedicine.org/kimmel_cancer_center/research/gi_spore/

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