Cynthia L. Sears, M.D.
Johns Hopkins University School of Medicine
Project: Gut microbiome and the immune microenvironment of human primary and metastatic colorectal cancer.
Grant amount: $400,000 over 2 years
Awarded from: 2017-2019
Grant awarded in partnership with Cancer Research Institute, who contributed $200,000
Dr. Sears’ work focuses on a novel and exciting hypothesis around the role bacteria play in altering the tumor microenvironment and how they impede the immune system’s ability to target and eliminate colon cancer. Learn more about her work in the press release.
Dr. Sears is a Professor of Medicine, Oncology and Molecular Microbiology and Immunology at the Johns Hopkins University School of Medicine and the Bloomberg School of Public Health. She is the Microbiome Program Leader of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins and is Director of the Johns Hopkins Germfree Murine Facility. She is an infectious diseases expert who has studied the pathogenesis of enterotoxigenic Bacteroides fragilis (ETBF), both in the laboratory and in clinical settings, over the past 25 years. The current focus of the Sears laboratory is to determine how the microbiota and specific bacteria contribute to colon carcinogenesis. The Sears laboratory integrates studies in humans and mouse models, employing microbiology, bioinformatics and immunologic methods. Dr. Sears has been an active member of the Infectious Diseases Society of America (IDSA) for more than 20 years, serving the Society in numerous capacities. Since November, 2016, she is the Vice President of the IDSA Board of Directors.
Dr. Noel F.C.C. de Miranda
Leiden University Medical Center in the Netherlands
Project: Researching Early Onset (Under 50), Late-Stage Colorectal Cancer
Grant amount: $100,000 over 2 years
Awarded from: 2015-2016
Grant awarded in partnership with Michael’s Mission, who contributed $50,000
Dr. de Miranda’s research focus involves increasing the ability of immune cells to recognize and eliminate cancer cells in individuals affected by early-onset colorectal cancer. The immune system is able to recognize abnormal proteins created by cancer cells, and therefore this creates the potential to recognize and eliminate these cancer cells. Often, a vigorous anti-cancer immune reaction is not naturally generated in colorectal cancer patients. Dr. de Miranda’s research involved development of a strategy where cancer-specific proteins can be used to elicit immune responses against cancer cells. Cancer genomes will be analyzed by advanced sequencing technologies to determine which abnormal proteins can be used to stimulate anti-cancer immune responses in a personalized setting.
Dr. de Miranda has accumulated more than seven years of experience in the study of colorectal cancer. During his undergraduate internship he investigated some of the mechanisms that colorectal cancer cells employ in order to avoid being detected by the immune system. Later, this subject constituted the basis of his Ph. D. thesis. Because colorectal cancer remains one of the most frequent causes of cancer-related deaths, Dr. de Miranda has a strong drive to research this disease in order to improve therapies for patients.
Dr. Ho-Chou Tu
Children’s Hospital in Boston
Project: The Pluripotency Factors LIN28A/B Promote Colorectal Cancer Progression
Grant amount: $50,000
Awarded in: 2014
Colorectal cancer (CRC) is one of the most common human cancers worldwide, with approximately 1.2 million new cases per year. Despite a rich history of investigation into the molecular basis of tumor initiation and progression, CRC remains a major contributor to cancer-related mortality. To date, conventional surgery and cytotoxic chemotherapy are the most common treatments for CRC patients. Basic research built upon genetic modified mouse models (GEMM) has the great advantage of modeling tumor initiation, development and progression in the cancer cells’ native microenvironment. Many mouse models bearing mutations in the commonly mutated pathways in CRC have been established and are widely used in CRC studies. However, these models usually develop benign tumors that seldom progress to highly invasive or metastatic cancer, which are the main causes of CRC-associated mortality in humans.
Lin28 is an evolutionarily conserved gene with roles in stem cell renewal and pluripotency. In mammals, LINin28 and its paralog LIN28B are highly expressed in embryonic stem cells (ESC) and in the early embryos while they become almost undetectable in most adult tissues. However, high levels of LIN28A and/or LIN28B are observed in various cancer types including CRC. Mechanisms typically at play during early embryonic development and stem cell self-renewal are often aberrantly activated in cancer. Impaired differentiation is a common feature of advanced forms of malignancy in humans and many display an ESC-like gene expression profile. Here, the authors propose LIN28 as such an embryonic factor contributing to malignant transformation during CRC development. Preliminary data gleaned through LIN28-mediated transgenic murine models indicates the impact of the LIN28 pathway on CRC initiation, growth and progrssion. With this study, the authors aim to inform greater insights in designing novel targeted therapeutics for CRC treatment, and also to provide guidelines in future development of murine models that closely mimic late stage CRC.
Andrea Bertotti, M.D., Ph.D.
Istituto per la Ricerca e la Cura del Cancro, Candiolo, Italy
Project: Improving Targeted Therapy in Colorecal Cancer Through Xenopatients
Grant amount: $100,000
Awarded from: 2012-2013
Dr. Bertotti created a unique collection of “xenopatients”–mice which are implanted and living with more than 300 different human colorectal cancer tumors. Each tumor has been meticulously analyzed for gene expression, exome, and cell pathways. With this grant, he tested (in mice rather than in patients) how specific human tumors with defined genetics respond to specific drugs and combinations. Bertotti’s work also sped the search for biomarkers—tests that could predict which drug will work for an individual’s specific metastatic colorectal cancer.
Dr. Bertotti has already made a mark in colorectal cancer research. “Andrea has stood out as one of the most brilliant young scientists of our institution,” said Dr. Paolo Comoglio, Scientific Director of the IRCC. He led “a huge institutional effort” to create the library of genetically analyzed human tumors transplanted into mice. With those human tumor samples, the laboratory will focus on the 40 percent of human metastatic cancer samples in which the tumor is held stable—but does not shrink—when treated with Erbitux (cetuximab).
Using the mouse models, the lab tested a combination treatment, adding lapatinib (another drug which works similarly but in a different pathway than Erbitux). The scientists analyzed the cells, looking for biomarkers that predict response to the treatments, as well as other pathways for which new drugs could be developed.
Dr. Jon Chung
Johns Hopkins University School of Medicine
Project: Hedgehog Pathway Targeted Therapeutics for Metastatic Colorectal Cancer
Grant amount: $45,000
Awarded in: 2011
Dr. Jon Chung studied alternatives to the traditional Hedgehog signaling pathway in colon cancer cells. He explored crosstalk within the cell between the Hedgehog and Wnt pathways and screening for drugs that block both pathways at the same time, potentially stopping cancer development.
He also looked at how Hedgehog interacts with DNA damage pathways — research that could lead to treatment that would destroy metastatic cancer cells.
From Dr. Chung’s research proposal:
“The Hedgehog signaling pathway has recently emerged as another key player in colorectal carcinogenesis and this pathway is progressively activated during metastasis. The switch to Hedgehog pathway activation that occurs as tumors metastasize presents an opportunity for developing therapies for metastatic colorectal cancer. My project will focus on targeting the Hedgehog pathway.”
Hedgehog is a gene that is critical to the development of the human embryo. Signals controlled by the gene direct cells to express themselves as different parts of the body with different functions. When Hedgehog expression isn’t normal, its changes can lead to cancer, particularly cancer that spreads to distant sites (metastasizes).
Dr. Rona Yaeger
Memorial Sloan Kettering Cancer Center
Project: A Translational Study of Inhibiting AKT to Treat Colorectal Cancer
Grant amount: $30,000
Awarded in: 2010
Dr. Rona Yaeger studied the AKT signaling pathway in the cancer cell both clinically during a Phase II trial and in the laboratory, looking at how blocking the pathway affects cells.
- For advanced colorectal cancer patients with normal or wild-type KRAS, conducted a Phase II clinical trial of an AKT inhibitor — MK-2206. Her primary objective was to see if the oral drug shrinks tumors. She also measured time to cancer progression, survival time, and serious side effects of treatment.
- In the lab, she analyzed models of KRAS mutation, searching for ways to inhibit the PI3K/AKT pathway and/or the MEK/ERK pathway. Some KRAS mutated tumors may be sensitive to blocking one or both pathways, but she expected some will be resistant. Understanding both how KRAS mutant tumors respond to or resist MEK and AKT inhibition will help individualize patients in the future for clinical trials of drugs that target these pathways.
Jeffrey Chou, M.D., Ph.D.
Fred Hutchinson Cancer Center at the University of Washington
Project: Epigenetic Modulation of Colorectal Cancer Stem Cells for Immunotherapy
Grant amount: $30,000
Awarded in: 2009
Jeffrey Chou, M.D., Ph.D. studied ways to make colorectal cancer stem cells more vulnerable to the body’s own immune system.
He worked with both cell cultures and specially-bred mice to see if the drug decitabine increased levels of a specific protein that induces a strong immune response. If so, a combination of decitabine and a vaccine against that protein might be an effective treatment for advanced colorectal cancer.
Colorectal tumors are composed of different cell types. A small number of tumor cells have the ability to move from where they first developed to new sites in the body to establish new tumors. Cells with this property are called cancer initiating stem cells. These cells are particularly resistant to chemotherapy. Even if 99% of a tumor is killed by chemo or other therapy, but cancer stem cells remain, the tumor will grow back and continue to spread.
One way to destroy cancer stem cells is to harness the body’s own immune system to recognize them as a threat and eliminate them. Ordinarily, the immune system accepts the proteins in cancer as a normal part of the body and basically ignores them.
However special proteins known as cancer/testis antigens (CTAs) stimulate an immune response in many cancers. CTAs are only found in cells in the testicles, where they are invisible to the immune system, and in some cancers. Because they are not found in normal tissue outside of testes, an immune system attack on cells with CTA can target cancer and leave healthy cells alone, ideal for cancer treatment.
Unfortunately, colorectal cancer cells have very low levels of CTAs so treatments for advanced colorectal cancer that evoke immune response (immunotherapy) haven’t been very effective. However, preliminary data show that the drug decitabine increases CTA levels in many types of cancers allowing immune system cells to recognize and kill them.
One cancer/testis antigen (NY-ESO-1) induces strong immune responses in cancer cells. Immune cells called cytotoxic T lymphocytes (CTLs) that can specifically recognize and kill cells producing NY-ESO-1 have been discovered. When colorectal cancer cells are treated with decitabine in the laboratory NY-ESO-1-specific CTLs kill the cancer cells but not normal or untreated cells.
Dr. Chou built on this knowledge in his research, asking three questions:
- Will treating colorectal cancer stem cell cultures with decitabine increase the levels of NY-ESO-1 in those cells?
- If colorectal cancer cells are treated with decitabine and immunotherapy (cytotoxic T lymphocytes) and transplanted into mice, will the mice develop cancer?
- Can treating mice who already have cancerous tumors with decitabine slow tumor growth or destroy those tumors completely?
Dr. Yaguang Xi
University of South Alabama – Mitchell Cancer Institute
Project: Micro RNA, Novel Prognostic Biomarkers in Colorectal Cancer
Grant amount: $30,000
Awarded in: 2008
Dr. Yaguang Xi was awarded Fight Colorectal Cancer’s first Research Fellows Grant. Dr. Xi’s grant, which was competitively awarded through the American Association for Cancer Research peer review process, had two parts.
In his prior research, Dr. Xi looked for micro-RNA, tiny bits of genetic material which help regulate cellular functions. He identified a number of micro-RNA which had higher levels in colorectal cancer cells than in normal cells.
During the first part of his grant-sponsored research, Dr. Xi examined the impact high levels of these specific micro-RNAs have on how sensitive cancer cells are to chemotherapy with 5-FU, Eloxatin, and Camptosar. If cells from tumors with high levels of micro-RNAs don’t respond well to these drugs, it could indicate that reducing the amount of these micro-RNAs in cancer cells may increase the effectiveness of chemotherapy, thereby identifying a promising new method to improve treatment for colorectal cancer.
In the second part, Dr. Xi looked for micro-RNAs in the tumors of hundreds of people with stage II or III colorectal cancer who had a recurrence, and attempt to determine if the presence of specific micro-RNAs correlate with a favorable or unfavorable patient outcome. This study might provide markers to identify patients who need aggressive adjuvant treatment after surgery to prevent recurrence.
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