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Last Updated: 08/31/20

MD Anderson Cancer Center SPORE in Gastrointestinal Cancer

The University of Texas MD Anderson Cancer Center

Principal Investigators:

Scott Kopetz, MD., PhD
Scott Kopetz, MD., PhD
Anirban Maitra, MBBS
Anirban Maitra, MBBS

PRINCIPAL INVESTIGATOR CONTACT INFORMATION

Scott Kopetz, MD, PhD
Associate Professor of Medicine
Department of Gastrointestinal Medical Oncology
The University of Texas MD Anderson Cancer Center
1515 Holcombe Blvd. Unit 426
Houston, Texas 77030
Phone: 713-792-2828
Email: skopetz@mdanderson.org

Anirban Maitra, MBBS
Professor of Pathology and Translational Molecular Pathology
Department of Pathology
University of Texas MD Anderson Cancer Center
1515 Holcombe Blvd. Unit 85
Phone: 713-745-0861
Email: amaitra@mdanderson.org

OVERVIEW

CRC is the 2nd most common cause of cancer-related deaths in this country, while PDAC is the 3rd most common cause, underscoring the significance of the work undertaken in this proposal. Our multidisciplinary team will conduct highly innovative translational research including first-in-human trials in order to further therapeutic options available to CRC and PDAC patients.

The MD Anderson SPORE in Gastrointestinal cancer is focused on having a clinical translational impact on colorectal (CRC) and pancreatic cancers (PDAC). The current challenges in this field are 1) failure of current immunotherapy agents to improve metastatic CRC outcomes, with the exception of rare subsets representing <5% of patients with microsatellite instability, 2) the slow pace of chemoprevention research and limited repertoire of agents being evaluated in the clinic for populations at-risk for CRC, and 3) necessity to explore novel therapeutic vulnerabilities and eliminate residual disease after standard of care chemotherapy in PDAC Our SPORE will address each of these challenges by building on strong preclinical data, unique opportunities, outstanding investigators, and well-supported environment. Led by Drs. Scott Kopetz and Anirban Maitra, this team of investigators with expertise in multidisciplinary translational research and clinical care of CRC and PDAC will achieve these goal through the following aims:

  • To evaluate clinical activity of an optimized combination of immune checkpoint inhibitors with a personalized, neo-antigen peptide vaccine (Project 1).
  • To determine the contribution of STAT3 signaling to CRC development in high-risk patients with familial syndromes or inflammatory bowel disease (Project 2).
  • To evaluate oxidative phosphorylation as a therapeutic vulnerability in pancreatic cancer (Project 3).

An Administrative Core designed to maintain fiscal responsibility along with reporting and institutional compliance will support all three projects. A Biospecimen and Pathology Core will support all clinical and research biospecimen needs for the four projects and a Biostatistics and Bioinformatics Core will provide support for trial design and biostatistics. Established working relationships have been extremely productive on many fronts from a well-positioned team approach. Our overall GI SPORE team is strategically organized to effectively translate our preclinical concepts and novel targets rapidly into a clinical setting, with the goal of significant impact on mortality rates from CRC and PDAC.

PROJECT 1: Personalized Adjuvant Immunotherapy for High-risk Colorectal Cancer

Project Co-Leaders:
Gregory Lizee, PhD (Basic)
Michael Overman, MD (Clinical)
Patrick Hwu, MD (Clinical

Immunotherapy with antibodies targeting checkpoint blockade molecules PD-1 and CTLA-4 has not demonstrated clinical activity in the vast majority of colorectal cancers (CRC). By contrast, a rare subset of CRC tumors that show microsatellite instability (MSI-high) demonstrate marked responses to PD-1 therapy, similar to or exceeding that observed in other highly mutated cancers such as melanoma and lung adenocarcinoma. This correlation of mutational load and clinical response suggests that the anti-tumor immunity generated by checkpoint inhibitors is mediated largely through the activation of T lymphocytes recognizing mutated peptides presented by HLA class I molecules at the tumor cell surface. While identification of mutated peptide epitope targets in individual patients remains a daunting technical challenge, recent advances in next generation sequencing (NGS) has provided a strong foundation on which to build these efforts. This approach holds the promise of a more personalized and focused method of activating anti-tumor immunity and is a fundamental component of a potentially powerful combinatorial strategy involving immune checkpoints and other immune stimulators. Identifying tumor-associated mutated target antigens in individual cancer patients would facilitate a “precision immunotherapy” strategy in which an immune response against multiple expressed tumor antigens could be generated in patients using multivalent peptide vaccines. Although non-mutated tumor-associated antigens can also be considered as suitable CTL targets in cancer therapy, targeting mutated neo-epitopes have the advantage of being more immunogenic and tumor-specific. However, many fundamental questions remain regarding choice of optimal antigens and adjuvants to use for generating both effective and sustained T-cell immunity in cancer patients through vaccination.

The specific objective of this proposal is to generate an effective, personalized vaccine approach for treatment of metastatic CRC patients at high risk of recurrence following surgery. Specifically, we will test the hypothesis that a vaccination strategy targeting multiple mutated CRC tumor antigens along with specific combinations of immune adjuvants will be capable of preventing recurrence in minimal residual disease (MRD) setting in post-hepatectomy CRC patients. As the success of vaccination is likely predicated upon lower volume disease, we propose to investigate our personalized peptide vaccination approach in CRC patients in the adjuvant setting who have detectable mutations in circulating tumor-derived DNA (ctDNA) that can be monitored over time. Our Preliminary Data shows that the proposed personalized vaccination strategy is feasible, as several CRC patients have now undergone vaccination in ongoing clinical trial at UTMDACC. In addition, our pre-clinical mouse data has shown that Toll-like receptor ligands, anti-CD40, and checkpoint blockade can be highly effective combinations of adjuvants in vivo. However, it is critical to understand the optimal combination of agents to use for vaccination in order to translate these findings into more effective vaccine strategies for our CRC patients.

PROJECT 2: Targeting STAT3 to Prevent Colorectal Cancer (CRC) in Hereditary Syndromes and Inflammatory Bowel Disease

Project Co-Leaders:
David Tweardy, MD (Basic)
Eduardo Vilar-Sanchez, MD., PhD (Clinical)

Evidence is increasing that signal transducer and activator of transcription (STAT) 3 contributes to sporadic and high-risk colorectal cancer (CRC) carcinogenesis arising in a background of inflammation such as inflammatory bowel disease (IBD), and also hereditary populations such as familial adenomatous polyposis (FAP) and Lynch syndrome (LS). However, questions remain regarding the contribution of STAT3’s signaling on the epithelial and stromal compartments in early stages of premalignancy development and the effects of targeting STAT3 in these patient populations. These questions are the significant gaps in knowledge that form the focus of Project 2, which is the designated prevention project for this GI SPORE.

IBD presents as either ulcerative colitis (UC) or Crohn’s disease (CD), the causes of which have yet to be identified, but it constitutes an attractive model to study the contribution of inflammation to colorectal carcinogenesis. There are two isoforms of STAT3 (α and β) derived from a single gene by alternative mRNA splicing that are expressed in cells at a 4:1 ratio (α:β). STAT3α is proinflammatory and anti-apoptotic, while STAT3β antagonizes these effects of STAT3α. We demonstrated that IBD in mice induced by either dextran sodium salt (DSS; UC model) or trinitrobenzoic acid (TNBS; CD model) was more severe in transgenic mice expressing only STAT3α compared to wild type mice. In addition, working in collaboration with StemMed, Ltd., a pharmaceutical company, we developed a potent small-molecule STAT3 inhibitor, C188-9, that targets the phosphotyrosyl peptide-binding pocket within the STAT3 SH2 domain thereby blocking STAT3 binding to its phosphotyrosyl ligand and inhibiting cytokine-mediated STAT3 activation [phosphorylation on tyrosine (Y) 705, pY-STAT3]. C188-9 administration prevented IBD caused by both DSS and TNBS. In studies by others, mice deficient in STAT3 in their intestinal epithelial cells demonstrated reduced tumor size and reduced tumor incidence in a model of colitis-associated CRC [azoxymethane (AM) plus DSS]. FAP is caused by germline mutations in APC. Genetically reducing levels of STAT3 in ApcMin/+ mice (ApcMin/+STAT3+/-) decreased the number of intestinal polyps compared to ApcMin/+STAT3+/+ mice. LS is an autosomal dominant disorder caused by germline mutations in one of the DNA mismatch repair (dMMR) genes, including MLH1, MSH2, MSH6, and PMS2. STAT3 activation results in extra-nuclear sequestration of MSH3, which may further impair dMMR in LS enterocytes bearing a mutation in one of the other dMMR enzymes resulting in increased risk of CRC. Our preliminary data using a CLIA-certified pY-STAT3 IHC stain and scoring system supports the activation of STAT3 signaling in normal-appearing mucosa that is further increased in CRC samples from IBD, FAP and LS patients.

The long-term goal of Project 2 is to determine if C188-9 will be of benefit in the prevention of CRC. The central hypotheses are that STAT3 contributes to CRC development in patients at risk for CRC and can be targeted successfully with C188-9. The objectives are to determine the effects of targeting STAT3 with C188-9 for prevention of CRC in mouse models and the contribution of STAT3 signaling to CRC development in IBD, FAP, and LS patients.

PROJECT 3: Inhibiting Oxidative Phosphorylation in Pancreatic Cancer

Project Co-Leaders:
Giulio Draetta, MD., PhD (Basic Co-leader)
Gauri Varadhachary, MD (Clinical Co-leader)

Pancreatic ductal adenocarcinoma (PDAC) contributes to 6.9% of all cancer deaths in the US, and >1.5% of the US population will be diagnosed with PDAC in their lifetime. At present, the front-line therapy for advanced PDAC is multi-agent chemotherapy, most commonly, FOLFIRINOX or gemcitabine and nab-paclitaxel. Despite a better understanding of the genomic landscape and the importance of the tumor microenvironment, there has been no meaningful shift in the overall survival for this disease. Thus, new therapeutic strategies for this deadly disease represent an urgent unmet clinical need.

Over 90% of PDAC harbor activating KRAS mutations, which are an early event in disease pathogenesis as they are present in pancreatic intraepithelial neoplasias (PanINs), the precursor lesion for PDAC. An emerging concept is that mutations in KRAS and other canonical oncogenes that drive accelerated growth also directly reprogram cellular metabolism by augmenting nutrient acquisition, coupled to an increased flux through downstream metabolic pathways. Increasingly, inter- and intra-tumoral heterogeneity in PDAC are appreciated, including KRAS dependency. It has been shown that cancer cell lines harboring mutant KRAS differ in their dependence on KRAS, implying plasticity either in reliance on KRAS signaling or a cell-type specific role for mutant KRAS in cells of different origin or lineages, or both. This idea has been further solidified in recent classifications of PDAC by subtype, where Collison et al. demonstrated that classical subtype PDAC lines were relatively more dependent on KRAS and exhibited an enriched signature of KRAS addiction compared with mesenchymal lines. Differential dependence on KRAS has also been linked with altered metabolic dependencies. In one specific context, our group used an inducible oncogenic Kras-driven PDAC model to demonstrate that, upon extinction of oncogenic Kras, the persistent Kras-independent tumor-initiating cells (TICs) exhibited a metabolic profile very different from that of the Kras-dependent cancer cells of the bulk tumor. Whereas the Kras-dependent cancer cells of the bulk tumor exhibited high levels of glycolysis and metabolic dependencies as described above, the Kras-independent TICs showed impaired glycolysis and increased mitochondrial respiration. Similar observations were made in TICs derived from human PDAC PDX models, which exhibited decreased glucose flux through glycolysis and elevated OXPHOS activity. These TICs harbor limited metabolic plasticity, rendering them particularly sensitive to inhibition of mitochondrial activity. Similar OXPHOS-addicted subpopulations with TIC properties have also been identified in other cancer types, such as melanoma and leukemia.

These findings indicate that the heterogeneity of PDAC is not only defined on the genomic and cellular levels, but also defined by distinctive metabolism programs controlled by oncogenic signaling. However, to date, the documented dependency of some tumors or tumor cell subpopulations on OXPHOS has not yet been exploited therapeutically. The University of Texas MD Anderson Cancer Center Institute for Applied Cancer Science (IACS) has developed IACS-010759, a potent inhibitor of complex I of the electron transport chain. The IACS compound has enabled expanded studies of OXPHOS inhibition in PDAC models that establish the preclinical rationale for evaluating IACS-010759 in patients in two contexts: (i) patients with treatment-naïve or refractory tumors that possess intrinsic sensitivity to OXPHOS inhibition, and (ii) in metabolically adapted disease following treatment with chemotherapy. We will explore the biology of response to treatment with IACS-010759 in these contexts, using a combination of ex vivo and in vivo studies, as well as evaluating patient response via clinical correlatives (transcriptomic signatures, hyperpolarized pyruvate-magnetic resonance imaging, quantitative CT scan) in planned phase 1b and phase 2a clinical studies in patients with treatment-naïve or refractory disease (phase 1b) or patients who have responded to prior standard-of-care chemotherapy (phase 2a).

CORE 1: ADMINISTRATIVE CORE

Core Directors:
Scott Kopetz, MD., PhD
Anirban Maitra, MBBS
David Menter, PhD

The Administrative Core (Core 1) will be responsible for the successful execution and management of all SPORE activities related to financial oversight and coordination, organization of all necessary meetings, and publicity and record keeping for all projects and the two other cores. This group will also provide regulatory oversight activities for clinical trials; ensure compliance with all institutional, federal, and NCI-specific regulations; and oversee the peer-review and oversight processes of the Career Enhancement Program and Developmental Research Program. The core will be led by Drs. Scott Kopetz, Anirban Maitra and David Menter.

CORE 2: BIOSPECIMEN AND PATHOLOGY CORE

Core Directors:
Dipen Maru, MD
Huamin Wang, MD, PhD

The Biospecimen and Pathology Core (Core 2) will coordinate efforts related to collection, processing, storage and distribution of annotated human and murine biospecimens for all of the SPORE projects, including the Career Enhancement Program (CEP) and Developmental Research Program (DRP). The Core will be co-led by two nationally reputed gastrointestinal/pancreatic pathologists, Drs. Dipen Maru and Huamin Wang. For human biospecimens, the core will interface with the MDACC Institutional Tissue Bank (ITB). Biospecimen resources from the lower gastrointestinal tissue bank include freshly collected/snap frozen and formalin fixed paraffin embedded tumor and normal specimens from more than 2500 resected hepatic colorectal metastases (including TMAs), freshly collected and snap frozen adenoma from 334 patients and formalin fixed paraffin embedded specimens from 870 or more patients with sporadic adenoma or familial adenomatous polyposis. Existing biospecimen resources available in the pancreatic bank and related IRB approved protocols include freshly collected/snap frozen tumor and normal tissue sample from Whipple resection for pancreatic ductal adenocarcinoma from 232 patients, with formalin fixed paraffin embedded specimens and additional 672 patients, including tissue microarrays from pancreatic ductal adenocarcinoma and intraductal pancreatic mucinous neoplasms.

The Core will support Project 1 by coordinating prospective blood collection, cryopreservation and transport with the ITB. Specifically, Core faculty will prospectively collect, process and distribute fresh tumor and normal samples from hepatic colorectal metastases after obtaining mirror image section for histology quality control. The Core will provide formalin fixed paraffin embedded samples of normal, adenoma and carcinoma to Project 2. In addition, the Core will provide biospecimen qualification services, including but not limited to, histopathologic characterization of human and murine tissues treated with STAT3 inhibitor, and immunohistochemistry staining and interpretation, including validation of p-STAT3 staining by automated image analysis in a CLIA-certified facility. The Core will provide freshly resected PDAC samples for patient derived xenografts and ex vivo live tissue sensitivity assay (LTSA) for Project 3. In addition, the Core will provide histopathology characterization, immunohistochemistry services and interpretation guidelines for both preclinical samples from the ongoing co-clinical trials, as well as serial tissue biopsies obtained from the two clinical trials being conducted in Project 3. The Core will also coordinate distribution of appropriate samples to investigators funded through the SPORE CEP and DRP grants. The Core personnel, along with the ITB, will enter detailed information related to all processes of biospecimen collection, processing, qualification, distribution and analytes extraction into the Institutional Biospecimen Informatics platform known as “Tissue Station”. The Core activities will lead to enhancement of these functionalities of Tissue Station and design a new interface specific for GI SPORE in the Tissue Station.

CORE 3: BIOSTATISTICS AND BIOINFORMATICS CORE

Director
Jeffrey Morris, PhD

The Biostatistics and Bioinformatics (Core 3) provides comprehensive service to guide design of experiments, to optimize quantitative data analysis, and to maintain statistical justification and interpretation of results. Specifically, Core 3 will implement sound experimental design principles that are tailored to address specific scientific questions for each project. Core 3 will also carry out data analyses using suitable statistical methods and bioinformatics algorithms and will contribute to the interpretation of results through written reports and frequent interactions with project investigators. Whenever appropriate, Core 3 will develop new analysis tools to address new challenges in the analysis of various data, especially high-throughput genomic and proteomic data. Members of Core 3 will participate in monthly SPORE meetings with all project investigators, ensuring that statistical and data analysis/management issues are carefully considered during all phases of each SPORE experiment. Thus, from inception to reporting and publication, basic laboratory and translational experiments will benefit from the SPORE program that will be used to augment existing MD Anderson Cancer Center biostatistics resources.

DEVELOPMENTAL RESEARCH PROGRAM

Directors:
Scott Kopetz, MD., PhD
Anirban Maitra, MBBS

The purpose of the Developmental Research Program (DRP) is to fund highly innovative translational studies in colorectal cancer (CRC) or pancreatic cancer (PDAC) that currently lack a human endpoint as mandated by the SPORE guidelines, but that could become full SPORE projects with requisite DRP support or compete successfully for funding outside of the SPORE mechanism. The DRP provides a unique venue for making available critical financial support, as well as disease-specific intellectual and resource expertise, through a program that is rapidly responsive to new ideas or initiatives, including from investigators whose current work may not focus exclusively in CRC or PDAC research. This program is rooted in a spirit of collaboration espoused by the GI SPORE leadership, which has an extensive track record of bringing investigators from other disciplines into the field of CRC and/or PDAC research. The strength of the DRP rests in its ability to make available financial support needed to access all the critical expertise and resources within the entire GI SPORE, including the proposed Cores. This will allow us to develop innovative, investigator-initiated projects that have the potential to flourish into reliable and productive translational research projects along a path from basic and/or population research projects into research focused on human clinical specimens/patient populations.

The DRP will be co-led by principal investigators of the SPORE including Dr. Anirban Maitra, the Scientific Director of the Sheikh Ahmed Center for Pancreatic Cancer Research, and Professor in the Departments of Pathology and Translational Molecular Pathology at UT MD Anderson Cancer Center (UTMDACC) and Dr. Scott Kopetz, Associate Professor and Deputy Chair for Translational Research in the Department of Gastrointestinal Medical Oncology. The DRP will incorporate UTMDACC, collaborating partner institution Johns Hopkins University (JHU), and other centers of excellence within the Texas Medical Center to provide an unprecedented seedbed for promoting innovative translational research projects in PDAC and CRC. Preproposals in the form of one-page letters of intent (LOI) will be solicited by the Program, and following review by the DRP leadership, applicants of the responsive pre-proposals will be invited to submit a full proposal for review. The DRP Directors will help investigators submitting proposals to formulate translational research aims and plans relevant to the overall themes of the GI SPORE, as many applicants may not have prior expertise in this type of research. The overarching goal will be to facilitate research activities that will enable proposing a feasible human endpoint for future iterations of the funded proposal. This process will therefore be a major educational activity that is further anticipated to stimulate translational research in CRC or PDAC and encourage the participation of both basic science researchers and clinical investigators in translational research.

CAREER ENHANCEMENT PROGRAM

Directors:
Scott Kopetz, MD, PhD
Elizabeth Jaffee, MD

The Career Enhancement Program (CEP) is designed to identify, recruit, and mentor junior scientists, including underrepresented investigators (minorities and women), for performing translational research in pancreatic (PDAC) and colorectal cancer (CRC). Fellowship training for physicians in gastrointestinal oncology and gastrointestinal pathology usually emphasize clinical care and clinical trials. Few graduates of such programs receive training that allows them to develop independent laboratories or translational research programs. Likewise, research specifically related to gastrointestinal cancer is not well represented in the basic sciences. Thus, there is a shortage of physician-scientists and basic scientists working in translational pancreatic and colorectal cancer research. Investigators supported under this Program will develop new innovative ideas that can improve prevention, diagnosis, or treatment of PDAC and CRC to improve quality of life for these patients and survivors.

Enhancing the development of innovative translational researchers in PDAC and CRC is critically dependent on the availability of flexible funding for career enhancement projects. The purpose of the Gastrointestinal Cancer SPORE CEP is to identify and develop such translational research investigators. The long-term goal of the CEP is to encourage investigators to develop research projects that will ultimately lead to clinically testable hypotheses. Both clinical and laboratory-based researchers are eligible for funding as long as they are proposing projects that are translational in nature. A portion of the SPORE budget ($100,000 per year) will be allocated annually to support these investigators. MD Anderson and Johns Hopkins are committing another $150,000 to support the CEP program.