Supporting leading researchers

Case Comprehensive Cancer Center’s Kishore Guda, DVM, PhD. will investigate how multifactorial mechanisms involved in colon tumor progression in African Americans contribute to higher colon cancer burdens in that population. African Americans have the highest colorectal cancer incidence and mortality rates in the United States.
 
Dr. Guda will discover and validate whether these colorectal cancer disparities are influenced, in part, by biological factors within patient tumors. The study is designed to decode the role of tumor biology as well as socio-demographic factors that jointly contribute to racial disparities in colorectal cancer outcomes. Overall, the study will inform the development of new biomarkers and therapeutic strategies.

Dr. Guda led the team that reported the first characterization of mutational and copy-number landscapes of colon cancers in the African American population (PNAS, 2015; Genome Medicine, 2015), identifying EPHA6 as a novel candidate driver gene in colorectal cancer. Dr. Guda also led the efforts to determine the phenotypic role of EPHA6 in colorectal cancer by developing a genetically engineered colon cancer cell line model harboring mutations in EPHA6, as well as a transgenic Epha6null mouse model whose phenotype he recently characterized to interrogate the function of EPHA6 in the colon. 

Dana-Farber Cancer Institute’s Kimmie Ng, MD, MPH, will investigate how the microbiome is different in CRC patients diagnosed with CRC at an age younger than 50 years old, compared to older patients and healthy individuals, and then examine whether those differences lead to worse tumor growth and weakened immunity against cancer, particularly among the youngest patients in their 20s and 30s. Young-onset colorectal cancer, which is CRC occurring in people under age 50, is a critical field of study as incidence rates have increased 2% every year since 1990, and today nearly 10% of CRC patients are under 50. 

Findings from Ng’s project will provide a better understanding of what an “unfavorable” microbiome is within each decade of life, and what impact that has on the body’s immune system to protect against CRC. The knowledge will then be used to discover new ways to change the microbiome to improve the immune response against CRC and develop more precise ways to screen and treat people at different stages of life.  

“The underlying causes of young-onset colorectal cancer are currently unknown, but we suspect that dietary and environmental factors may be influencing the microbiome, leading to increasing rates among young individuals,” said Ng who is the director of the Young-Onset Colorectal Cancer Center at Dana-Farber/Brigham and Women’s Cancer Center. “This grant from the Colorectal Cancer Alliance will support a large research effort to further investigate the impact of the microbiome on development of colorectal cancer in patients across the spectrum of young age, compared to older patients with colorectal cancer.”
 

Summary: Rectal cancer will be diagnosed in more than 43,000 people in the United States in 2018. Rectal cancer is particularly challenging, as treatment after diagnosis is more complex compared to colon cancer due to tumor location in the pelvis and proximity to organs important for bowel, sexual and urinary function. Further, rectal cancer is on a sharp rise in patients <50 years of age and there are no current models of rectal cancer. Despite the fact that rectal cancer is treated differently from colon cancer by using chemoradiation before surgery, the data used to inform rectal cancer clinical trials has historically relied on colon cancer cell lines as a preclinical model system, highlighting the need to use patient-specific models to better study this disease. Furthermore, efforts to derive organoid “biobanks” have focused primarily on colon cancer specimens, thus a preclinical biorespository of rectal cancer tissue or organoids remains an unmet need. Unfortunately, no targeted therapy exists in rectal cancer patients who have few to no options if standard treatment is ineffective. There is desperate need for better models of rectal cancer, as current methodologies (e.g., cell lines or patient-derived xenografts) do not represent rectal cancers well. Our recent work shows that rectal cancer tumoroids derived from pre-treatment biopsies and from specimens resected in the operating room develop into structures identical to the primary tumor. Based on this work we are now poised to significantly increase the reagents available to study individual rectal cancers. We have the unique ability to implant and grow these tumoroids in the mouse rectum (similar to human disease) and can monitor them in real time by endoscopy. A surgeon with a focus and expertise in rectal cancer who is also a dedicated physician-scientist is critical to moving this work forward and discovering better treatments for rectal cancer patients.

Summary: A number of studies indicate that colorectal cancer (CRC) occurring in younger versus older individuals differs in many ways that affect prognosis and success of treatment, with standard therapies less effective in young patients. Treatment of CRCs in young individuals poses specific burdens, including issues of fertility and early menopause for women, and issues of potency for men. In addition, economic productivity and caregiver demands for both children and parents are high at this age. Therefore, it is important to optimize outcomes, while minimizing toxicity, for young patients. An accurate picture of the genetic profile of tumors arising in young CRC patients is necessary for progress toward these goals. However, due the complexity of mutational patterns found in tumors, and the limited number of cases so far available to analyze, the specific genetic features of young versus old colorectal cancer patients remain poorly described. In Aim 1 of this proposal, we will leverage a unique dataset for over 14,000 colorectal cancer patients (including over 3700 < age 50), containing extremely detailed information on 19 CRC-relevant genes for each patient, along with extensive clinical context, plus a complementary data set on >7,500 CRC patients with information on up to 315 gene sequences. We will characterize the specific genomic alterations of young CRC patients that will lead to a better understanding of the molecular drivers in these patients. In Aim 2 of the proposal, we will test the impact of the age-related mutational patterns defined in Aim 1. We will query 3 publicly available databases containing data on clinical outcomes (overall survival, cancer-specific survival) not present in our primary data set, that will enable us to confirm the functional importance of differences found in Aim 1. Based on this analysis, we will for the first time be able to thoroughly characterize young onset CRC, and identify novel targets for therapy in this understudied group.

Summary: With incidence increasing at 1.5-2% each year for the last 20 years, colorectal cancer affecting young individuals (YO-CRC) is a growing health problem that is weakening the success of early detection of CRC. YO-CRC may be overrepresented by a different type of cancer, because it often presents at an advanced stage, it is more aggressive and it is often located in the left side of the colon or in the rectum. However, the biological definition of YO-CRC has been limited. In the absence of this knowledge, our ability to design strategies for prevention or early detection of YO-CRC will remain limited. Our overall objective in this proposal is to identify the key biological elements that drive the development of a novel CRC type we have recently described. In a set of CRC cases affecting young individuals, we found that CRCs without alterations in the tumor gene APC (APC negative CRCs) were associated with young age of diagnosis and these tumors had a set of marks in the tumor DNA that were not previously described. Therefore, our central hypothesis is that APC negative CRCs constitute a new CRC type that develops due to alterations in those DNA marks and it is overrepresented in YO-CRC. To test our hypothesis, we will: (1) Identify the DNA marks that define APC negative CRCs and (2) Identify the key biological elements that are controlled by the alteration of those DNA marks in APC negative CRCs. Characterization of the biologic elements that results from alterations in DNA marks will help explain how the cells that initiate the cancer can develop into a tumor without altering the key APC gene in what appears to be a novel mechanism. The outcomes of the proposed aims will thus provide essential knowledge on how APC negative CRCs develop, which is crucial in the development of potential treatments and in the design of effective early detection tests.

Summary: While the incidence of colorectal cancer (CRC) in those over 50 years old has been decreasing in the United States, the incidence in those under age 50 is increasing. The cause of this increase is unclear, and the characteristics of these patients are not fully understood. More research is critical to understand the underlying mechanisms of CRC in those under 50 to help better understand prevention strategies to improve care and outcomes.

Early studies have suggested that changes in the gut microbiome, which is composed of the bacteria, viruses, fungi and other organisms that inhabit the gastrointestinal tract, can contribute to the development of CRC. We also know that the microbiome can be affected by diet and antibiotics. With the widespread use of antibiotics, the addition of antibiotics to the food source, and changes in dietary habits, there is a critical need to better understand the gut microbiome composition and its contribution to young onset CRC. With the recent opening of the Center for Young Onset Colorectal Cancer at Memorial Sloan Kettering Cancer Center (Center Co-Directors: Robin Mendelsohn, PI and Andrea Cerceck, co-PI), we are uniquely suited to study this patient population.

The objective in this application is to describe the gut microbiome of patients under the age of 50. We will compare the microbiome of these patients to two groups: 1) a national database of microbiomes of young healthy patients and 2) people with CRC over the age of 50. We will therefore be able to see if there are differences between the microbiome in those under 50 with and without cancer as well as between the microbiome of those patients under and over 50. We will also be distributing a diet and medication questionnaire to gain a better understanding of the exposures in this group.

This study will add new and significant insight into identifying the etiology of young onset CRC to help decrease the incidence and mortality from this potentially curable disease.

Dr. Christopher Lieu, MD is a member of the Developmental Therapeutics (Phase I clinical trials) and Gastrointestinal (GI) Medical Oncology Program.   These comprehensive programs include multidisciplinary cancer clinics, tumor boards, and research endeavors.  Dr. Lieu is interested in resistance mechanisms to targeted therapy in GI cancers, and he was awarded the Conquer Cancer Foundation Career Development Award and an NIH K23 grant to study targeted therapies in colorectal cancer.  Dr. Lieu is also investigating novel therapeutic strategies to treat more effectively or prevent colorectal cancer in young adults.

Edward Chu, MD is involved in basic, clinical, and translational cancer research. His basic research interests have focused on characterization of the molecular mechanisms underlying the development of cellular drug resistance, especially as it relates to the fluoropyrimidine class of anticancer agents. His research group was the first to identify translational autoregulation as a novel regulatory mechanism in eukaryotes for controlling the expression of the folate-dependent enzymes, thymidylate synthase and dihydrofolate reductase. His clinical translational research efforts have focused on identifying novel drugs and treatment strategies for colorectal cancer and other GI cancers and in developing early-phase I/II clinical trials. He has a strong interest in integrating Chinese herbal medicine with standard cancer chemotherapy with the goal of enhancing clinical activity and reducing the toxicity associated with chemotherapy.

John Marshall, MD is a global leader in the research and development of drugs for colon cancer and other GI cancers. He is the principal investigator of over 150 clinical trials, at the local as well as national levels. Dr. Marshall is the clinical director of oncology for Georgetown University Hospital, associate director for clinical care of the Lombardi Comprehensive Cancer Center, and chief of the Division of Hematology-Oncology. In 2009, Dr. Marshall became the founding director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancer. Combining expertise in molecular medicine, translational research, and a patient-centered philosophy, the Ruesch Center is dedicated to realizing the dream of individualized curative therapies through research, care and advocacy. Dr. Marshall’s own research focuses on the development of a novel vaccine for the treatment of advanced colon cancer. For over a decade, he has directed Lombardi’s Developmental Therapeutics Program while also maintaining his regular clinical practice. Seeing about 60 patients each week, Dr. Marshall specializes in cancers of the GI tract at all stages of the disease.