FAP Research Award

Genomic and Microenvironmental Determinants of Premalignant Progression in FAP Patients

Chrisina Curtis, PhD, MSc

• RZ Cao Professor of Medicine, Genetics & Biomedical Data Science and Sr Vice Chair of Research, Department of Medicine, Stanford Medicine

• Director AI and Cancer Genomics, Stanford Cancer Institute

• Investigator, Chan Zuckerberg Biohub

Genomic and Microenvironmental Determinants of Premalignant Progression in FAP Patients

Familial adenomatous polyposis (FAP) is a rare inherited condition that greatly increases the risk of colorectal cancer (CRC). Nearly all patients with FAP will develop CRC if the colon is not surgically removed. This is caused by an inherited mutation in the APC gene, which normally helps control cell growth. When both copies of APC become inactive in colon tissue, small abnormal growths called adenomas can form, some of which may eventually progress to cancer.

Our research aims to understand why some precancerous changes in the colon progress to adenomas and cancer, while many others do not. We previously studied polyps from FAP patients and discovered that adenomas often arise from multiple cell lineages, not just a single mutated cell. Building on this work, we will study the earliest visible changes in colon tissue, known as aberrant crypt foci (ACFs). These microscopic lesions can contain abnormal cells, but most never progress further. By comparing ACFs that remain harmless with those that develop into adenomas, we hope to identify the key genetic and environmental triggers of progression.

We will investigate three main questions: (1) Do different inherited APC mutations change how quickly abnormal growths appear? (2) Which additional mutations drive the transition from ACFs to adenomas? (3) How do surrounding tissue and immune cells influence this process? By answering these questions, we aim to improve how CRC risk is predicted in FAP patients and to guide the development of preventive therapies that could stop adenomas before they form.

Chemoprevention in Familial Adenomatous Polyposis Through Menin Inhibition

Bryson Katona MD, PhD, AGAF, CGAF

• Jeffery and Cynthia King Associate

• Professor of Lynch Syndrome Research

• Executive Director, King Center for Lynch Syndrome

• Director, Gastrointestinal Cancer Genetics Program

• Associate Professor of Medicine and Genetics

• Division of Gastroenterology and Hepatology

• University of Pennsylvania Perelman School of Medicine

Chemoprevention in Familial Adenomatous Polyposis Through Menin Inhibition

This grant proposal will explore whether targeting the protein menin may serve as a novel chemoprevention approach for FAP.  We show that in mouse models of FAP where menin is not expressed, the mice develop a smaller polyp burden and have longer survival compared to FAP mice that express menin in their colons.  To further these preliminary data findings, in this proposal we will determine the mechanism whereby menin is promoting colon polyp growth, and whether this is specific to FAP or may also be applicable to other polyposis syndromes.  We will also test whether small molecule menin inhibitors, which are drugs that can be taken orally, can reduce growth of colon organoid models generated from patients with FAP and also reduce colon polyp development in FAP mice.  If successful, this investigation may define a novel strategy for chemoprevention in FAP that could potentially reduce CRC risk and the need for frequent colonoscopy and/or preventive colon surgery in FAP patients.

Targeting Bistable Stem Cell States in Response to APC Loss in FAP

Christopher Legner, PhD

• Chair, Department of Biomedical Sciences

• Member, Institute for Regenerative Medicine, Perelman School of Medicine

• Member, NIH P30 Center for Molecular Studies in Digestive and Liver Diseases, Perelman School of Medicine

• Director, Center for Animal Transgenesis

• Member, Abramson Cancer Center

Targeting Bistable Stem Cell States in Response to APC Loss in FAP

FAP is a tumor predisposition syndrome where epithelial cells of the intestine lose function of the tumor suppressor protein APC, resulting in the formation hundreds to thousands of precancerous polyps, some of which invariably progress to colorectal cancer.  For over a quarter century, the study of APC loss has focused on the oncogenic activity of a downstream transcription factor called Beta Catenin which promotes uncontrolled cell proliferation.  However, clinical observations indicate that colorectal tumors driven by APC loss are larger and more aggressive than those driven by oncogenic Beta Catenin mutations.  These observations lead to a hypothesis that APC inactivation results in additional oncogenic effects that we have yet to fully understand.  Recent work from our group has identified a second parallel pathway to Beta Catenin oncogenic activity downstream of APC loss.  Specifically, we identified a molecular mechanism resulting in the stabilization of an additional oncogenic transcription factor, YAP, which promotes a cell state similar to that seen in fetal intestinal development.  Remarkably, while both Beta Catenin and YAP-driven cell states are induced upon APC loss, they are mutually exclusive at the level of individual cells.  Further, these cell states are readily interchangeable over very short time periods (hours to days).  These observations provide insight into why traditional therapies targeting the Beta Catenin pathway have not been highly efficacious.  Our current work is focused on identifying therapeutic strategies to push APC-null cells into one state or the other, as well as concomitantly targeting both states in an effort to arrest tumor progression in FAP, and more broadly in colorectal cancers.

Immune Circuits in Duodenal Polyposis of Familial Adenomatous Polyposis

Jacob Nattermann, MD

• Professor of Hepatogastroenterology and Head of the Section for Hepatogastroenterology,

• Deputy Director of the Department of Internal Medicine I at Bonn University Hospital

Immune Circuits in Duodenal Polyposis of Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is an inherited condition that causes hundreds of polyps to grow in the intestine. While surgery can prevent colon cancer, polyps in the duodenum remain a major cancer risk and a leading cause of death in FAP patients. The disease progresses very differently among individuals, even within the same family, suggesting that additional factors such as immune regulation and the gut environment play an important role.

This project will:

1. Create a detailed “cell atlas” comparing immune and epithelial cells in duodenal tissue from FAP patients with mild and advanced disease, revealing which cell types and pathways are linked to faster polyp growth.

2. Use advanced computer modelling to integrate these data and predict which immune circuits drive disease progression and could represent potential targets for prevention or therapy.

The resulting maps and predictive models will provide new insight into how the immune system influences duodenal tumor development in FAP and could guide future efforts to delay surgery or design mechanism-based prevention strategies

Mapping High-Resolution Genomic Alterations in Familial Adenomatous Polyposis Using Long-Read Sequencing

Nilay Sethi, MD, PhD

• Assistant Professor, Dana-Farber Cancer Institute and Harvard Medical School

• Associate Member, Broad Institute

Mapping High-Resolution Genomic Alterations in Familial Adenomatous Polyposis Using Long-Read Sequencing

Familial Adenomatous Polyposis (FAP) is a hereditary condition that causes individuals to develop hundreds to thousands of precancerous polyps (adenomas) in the colon, driven by inherited mutations in the APC gene. While removing the colon can prevent cancer, we still lack a clear understanding of how and why these polyps form in the first place, or why some progress to cancer while others do not. This project aims to uncover the earliest genetic changes that trigger polyp formation in people with FAP.

To do this, we are using cutting-edge long-read DNA sequencing to analyze colon organoids - miniature, lab-grown versions of colon tissue - derived from patients with FAP. These organoids faithfully replicate what happens in patients’ colons and allow us to map changes in the genome with far greater detail than ever before. This technology can detect complex genetic alterations that are often missed by standard sequencing methods.

The ultimate goal of this research is to create a comprehensive map of early disease progression in FAP, leading to new strategies for early detection, personalized risk assessment, and targeted prevention. By understanding what goes wrong before cancer begins, we hope to empower the FAP community with new tools to protect their health and prevent disease progression without invasive surgery.

FAP Pilot Research Award

Identification of APC Synthetic Lethal Targets for FAP Treatment

Andres Blanco, PhD

• Assistant Professor of Biomedical Sciences

Identification of APC Synthetic Lethal Targets for FAP Treatment

Familial adenomatous polyposis (FAP) is an inherited condition in which tens to thousands of small growths – or, polyps – form in the rectum and colon in early adulthood. If FAP is left untreated, colorectal cancer (CRC) will develop in almost 100% patients by age 40. Due to this concern, FAP patients are subjected to annual colonoscopies and potentially to prophylactic surgery to prevent CRC. A potential alternative to surgical intervention is chemopreventative treatment – treatment with agents that prevent progression to CRC. While attractive in principle, successful chemopreventative approaches have not yet been developed. Here, we propose an approach to lay the groundwork for a novel type of chemoprentative FAP treatment. Our method is focused on a gene called APC – which is the gene that is universally mutated in FAP. We suspect that the APC mutation creates novel cellular vulnerabilities – or, cellular Achilles’ heels that are unique to the FAP cells – that can be targeted with drugs. Here, we will use the Nobel prize-winning CRISPR-Cas9 methodology to identify these genes that, upon inhibition of the proteins they encode, will prevent FAP progression to CRC. We will test the drugs we find using cellular models of FAP – colon cells with the APC mutation that can be grown on Petri dishes. If we are successful, colon cells treated with the drug(s) will retain normal growth properties, rather than growing dangerously fast and progressing toward CRC. In this case, such a drug could potentially be used for chemoprevention of CRC in FAP patients.

A Mouse Model for FAP Polyp Progression and Prevention

James M. Ford, MD, FASCO

• Professor of Medicine and Genetics

• Division of Oncology Director

• Clinical Cancer Genetics and Genomics

• Stanford University School of Medicine

A Mouse Model for FAP Polyp Progression and Prevention

Familial Adenomatous Polyposis (FAP) patients have a very high rate of polyp progression to colon adenocarcinomas unless undergoing a prophylactic colectomy. However, to date there is little that can be done clinically to prevent this in patients at high risk. We propose to develop a mouse model of FAP polyp progression to colon cancer and to use this to test the hypothesis that mutagenesis, and ultimately tumorigenesis, can be suppressed by activating specific DNA repair enzymes that recognize the most highly mutagenic lesions that arise in DNA. Our research team is the first to propose upregulating DNA repair as a targeted strategy for chemoprevention as there are currently no clinical strategies for directly suppressing mutagenesis. In Aim 1, we will feed ApcMin/+ mice, which have been genetically modified to develop intestinal polyps, with damaged deoxynucleosides that we have shown to introduce DNA damage and result in enhanced mutagenesis in cell lines, to accelerate the progression of polyps to invasive colon cancers in mice and thus more accurately mimic the physiologic condition of human FAP patients. In the second aim, we will test whether small-molecule activators of specific DNA repair enzymes that we have disovered will enhance DNA repair and suppress mutagenesis in our animal model of FAP. We hypothesize that FAP patients and others can benefit from the development of DNA repair targeted strategies for preventing the mutations that lead to malignancies, and thus serve as clinical prevention agents that might be exploited for FAP patients.

The Impact of Estrogens on Colorectal Polyp Burden in FAP

Bryson Katona MD, PhD, AGAF, CGAF

• Jeffery and Cynthia King Associate

• Professor of Lynch Syndrome Research

• Executive Director, King Center for Lynch Syndrome

• Director, Gastrointestinal Cancer Genetics Program

• Associate Professor of Medicine and Genetics

• Division of Gastroenterology and Hepatology

• University of Pennsylvania Perelman School of Medicine

The Impact of Estrogens on Colorectal Polyp Burden in FAP

In this grant proposal we will investigate whether estrogens can slow polyp growth in FAP.  Estrogens are natural hormones involved in the reproductive and sexual development of women, and there are four major types of estrogen.  Clinically, we have seen that women with polyposis, including FAP, who go through a pregnancy, develop a temporary stagnation or reduction in their polyp burden during pregnancy.  This indicates that it is possible that estrogens, which are increased during pregnancy, may be playing a role in preventing colon polyp growth.  We will test whether each of the four different estrogens is able to reduce the growth of colon and polyp organoids generated from FAP patients.  We will also test whether each of the four estrogens can prevent polyp growth in a mouse model of FAP.  If successful, these proposed experiments will define a novel strategy for chemoprevention in FAP that has potential to be directly translated to improving care, reducing morbidity, and reducing CRC cancer risk for FAP patients.

Tuft Cell–Derived Prostaglandin D2 as a Target for Chemoprevention in FAP

Ken S. Lau, PhD

• Professor of Cell and Developmental Biology

• Director of the Center for Computational Systems Biology

• Vanderbilt University School of Medicine

Tuft Cell–Derived Prostaglandin D2 as a Target for Chemoprevention in FAP

Chronic baseline inflammation and the resulting tissue damage are major risk factors for the development of precancerous lesions, particularly in individuals with Familial Adenomatous Polyposis (FAP), which is a hereditary disorder that predisposes the gastrointestinal tract to the formation of precancerous polyps. Thus, strategies that reduce inflammation prior to polyp formation represent an attractive chemoprevention approach for FAP.  This pilot project focuses on tuft cells, a rare epithelial cell type in the gut that senses the microbiome and modulates immune responses.  Tuft cells have been previously shown to suppress inflammation in models of inflammatory bowel disease. Specifically, we will investigate the function of prostaglandin D2 (PGD2), an immunomodulatory molecule that is produced uniquely by tuft cells in the gut. In this pilot, we will first use models of FAP to track tuft cell behaviors and PGD2 production throughout the course of disease. Then, we will assess how genetic ablation of tuft cells or PGD2 impacts polyp formation. The goal of this pilot is to determine whether the tuft cell-PGD2 axis is active and functionally relevant in FAP, potentially paving way for safer, more targeted, and personalized chemoprevention strategies for patients with this condition.

Chemoprevention in Familial Adenomatous Polyposis with Eicosapentaenoic Acid and Docosahexaenoic Acid

Jatin Roper, MD

• Associate Professor of Medicine

• Duke University School of Medicine

Chemoprevention in Familial Adenomatous Polyposis with Eicosapentaenoic Acid and Docosahexaenoic Acid

Familial adenomatous polyposis (FAP) is an inherited condition that causes colorectal cancer in 100% of patients without colon resection. After colon resection, the most common site of cancer is in the upper small intestine or duodenum. Cancers that develop in this area require complex surgery to treat. Therefore, drugs to prevent precancerous polyp and cancer formation in FAP patients are urgently needed. However, most drugs that have been tested in FAP carry significant side effects, so they are not practical for lifelong use. We discovered that fatty acids in fish oil inhibit cell membrane receptor related growth pathways that cause colon and duodenal cancer in FAP. Fish oil is a commonly used and safe dietary supplement. In this application, we propose a clinical study of fish oil to reduce polyp development in FAP patients. The goal of this study is to establish a new, effective, and safe option for prevention of cancer in FAP. 

CGA-IGC Research Award

In Vitro Evolution of Premalignant FAP Patient-Derived Organoids

Debra Van Egeren, PhD

• A.P. Giannini Postdoctoral Fellow, Stanford University School of Medicine

In Vitro Evolution of Premalignant FAP Patient-Derived Organoids

Patients with familial adenomatous polyposis (FAP) develop hundreds to thousands of colorectal polyps. Understanding how these growths potentially develop into colorectal cancer will help us prevent this disease in  individuals with FAP. To learn about this process, we will study how cells in these polyps acquire new abilities that cause them to turn into cancer. These new abilities can include cells being able to grow even when they receive signals to stop growing, or being able to invade nearby tissues or organs. We will examine polyps from FAP patients to see which individual cells have already developed these cancer-associated abilities by culturing these cells as organoids under conditions that only allow cells with these specific properties to survive. Additionally, we will continue to culture these patient-derived organoids in selection conditions that only allow survival of cells with these cancer-associated abilities to determine how and why they acquire this new capacity to develop cancer. Through DNA sequencing and other molecular profiling techniques, we will identify the mutations or other molecular changes that lead to cancer in these organoids. In the future, these causative mutations or molecular changes could be targeted by preventative strategies to reduce the risk of developing colorectal cancer in FAP patients.

Familial Risk and Predictors of Gastric Cancer in Familial Adenomatous Polyposis

Mehul Trivedi, MD

• University of Utah Gastroenterology, Hepatology and Nutrition Fellow

Familial Risk and Predictors of Gastric Cancer in Familial Adenomatous Polyposis

Gastric cancer (GC) has been increasingly observed as a significant cause of morbidity among patients with familial adenomatous polyposis (FAP) and estimates of the true incidence appear to be increasing. However, few population-based analyses of GC risk among FAP patients have been conducted. Current upper gastrointestinal surveillance guidelines note that optimal management and surveillance strategies are not known. This demonstrates a significant gap in management of gastric cancer risk. Recent observations from our institution suggest GC may cluster within certain families, raising a question of genetic and/or environmental influences on the APC mutation, and association with phenotypes such as GC risk.

Our objective is to identify genetic and environmental drivers of GC risk in FAP to improve risk stratification for better medical management. We aim to do this by assessing familial patterns of GC by leveraging the extensive genealogy and medical histories in the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR). We will evaluate the incidence of GC in FAP and in 1st, 2nd and 3rd degree relatives of FAP patients. Secondary aims are to identify predictors of GC in FAP.

This study would be among the first to utilize a population-wide genealogical database to investigate the familial risk of GC in this population, and the impact genetics may have on the development of gastric neoplasia. Findings from this work may allow for an improved understanding of GC in FAP and more tailored surveillance strategies