Other Cancers

Current Projects
Sylvan C. Baca, MD, PhD

Promising new treatments for cancers of the bladder and kidney have been developed, but, as with many cancer therapies, tumors eventually develop resistance. Research has shown that cancer cells resist treatment in part via epigenetic changes—those that do not affect the DNA sequence itself but turn important genes on or off, allowing cancers to survive under therapeutic stress. Dr. Baca is using novel techniques to study the epigenomes of cancer cells from blood samples. His goal is to understand how changes in the epigenomes of bladder and kidney cancers lead to treatment resistance. This knowledge will enable the design of better treatments and drug combinations that will benefit patients with metastatic bladder or kidney cancers.

Project title: "Epigenetic drivers of resistance to novel therapies for bladder and kidney cancer"
Institution: Dana-Farber Cancer Institute
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Toni K. Choueiri, MD
Cancer Type: Kidney and Bladder
Research Area: Epigenetics
Ben F. Brian, PhD

Abnormal interactions between our immune system and our gut microbes can lead to inflammation that drives colon and gastric cancer growth. Dr. Brian [HHMI Fellow] is investigating how the immune system recognizes and responds to these microbes, and how these interactions contribute to abnormal inflammation that can fuel cancer growth. Microbiota-immune interactions have been generally studied in the context of "clean" laboratory mice, but these models do not fully capture human immunology and the complex interplay between host cells and foreign microbes. To overcome this, Dr. Brian plans to study these interactions in "dirty" mice, colonized by a diverse community of microbes as well as pathogens. He will then use laboratory mice with more defined microbial communities to test how recognition of specific microbes by the immune system is regulated and how disruptions to this regulation contributes to inflammation. Dr. Brian received his PhD from the University of Minnesota, Twin Cities and his BS from the University of California, Santa Barbara.


Project title: "Mechanisms and consequences of microbiota-directed immune responses"
Institution: University of California, Berkeley
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Gregory M. Barton, PhD
Cancer Type: Gastric, Other Cancer, Colorectal
Research Area: Basic Immunology
Lauren E. Cote, PhD

Dr. Cote is exploring embryonic development to better understand how cells cooperate and build complex tissues. Since cancer cells often erroneously redeploy developmental programs and behaviors, her research into how neighboring cells align will yield insights into how cancerous cells metastasize and invade other tissues. Dr. Cote is combining tissue-specific genetic manipulations and laser cell ablations with live imaging during Caenorhabditis elegans digestive tract development to reveal how intracellular organization in one cell type can influence the alignment, polarity, and function of cells in the neighboring tissues.

Project title: "Constructing one continuous digestive tract, cell by cell"
Institution: Stanford University
Award Program: Fellow
Sponsor(s) / Mentor(s): Jessica L. Feldman, PhD
Cancer Type: Gastric, Other Cancer, Breast, Colorectal, All Cancers
Research Area: Developmental Biology
Allison L. Didychuk, PhD

Kaposi's sarcoma herpesvirus (KSHV) is a human oncogenic virus and the causative agent of cancers including Kaposi’s sarcoma, primary effusion lymphoma, and Multicentric Castleman disease. The related human herpesvirus Epstein-Barr Virus (EBV) is even more prevalent than KSHV, and is linked to cancers including Burkitt’s lymphoma, Hodgkin’s lymphoma, and nasopharyngeal carcinoma. Dr. Didychuk [The Rhee Family Breakthrough Scientist] is investigating the mechanisms by which KSHV co-opts the cellular host machinery to produce its own gene products in a manner distinct from other viruses and host cells. A molecular understanding of how herpesviruses hijack the late gene transcription machinery will reveal new therapeutic weaknesses in the viral lifecycle and allow for structure-guided design of novel anti-viral drug targets.

Project title: “Understanding the mechanism of genome packaging in oncogenic herpesviruses"
Institution: Yale University
Named Award: The Rhee Family Breakthrough Scientist
Award Program: Dale Frey Scientist
Cancer Type: Blood, Other Cancer, Sarcoma
Research Area: Virology
Brendan Floyd, PhD

Proteins found on the surface of cells are key agents in cancer progression, as they play a role in cell signaling and metastasis. Targeted protein degradation has emerged as a therapeutic strategy to modulate what are considered “undruggable” proteins. Specifically, lysosomal-targeting protein degradation (LTPD), which uses the cancer cell’s own degradation machinery to break down proteins, has demonstrated therapeutic potential. However, the proteins targeted for LTPD have been limited to a few well-studied membrane and extracellular proteins, leaving much still unknown about the breadth of proteins that can be targeted for degradation and the features of a target protein that determine LTPD efficacy. Dr. Floyd [HHMI Fellow] aims to systematically characterize the features of cell surface proteins that drive the efficacy of LTPD with the goal of identifying new targets for blood cancer treatment. Dr. Floyd received his PhD from University of Texas at Austin, Austin and his BS from California Polytechnic State University, San Luis Obispo.

Project title: "Systematic characterization of lysosomal-targeting protein degradation"
Institution: Stanford University
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Carolyn R. Bertozzi, PhD
Cancer Type: Other Cancer
Research Area: Chemical Biology
Catherine A. Freije, PhD

Dr. Freije [Berger Foundation Fellow] is studying how the genetic diversity of hepatitis B virus (HBV) is shaped by its need to replicate and interact with specific host genes. Current antiviral therapeutics for HBV merely suppress infection and do not cure disease; as a result, patients with chronic HBV infection are at risk of developing liver cancer. Dr. Freije plans to uncover essential genomic regions that HBV needs to survive and persist, as well as those that counteract host genes that function to restrict these activities. This approach could provide insight into the progression of disease and has the potential to identify new antiviral therapeutics and ultimately reduce the incidence of HBV-associated liver cancer.

Project title: "Investigating the role of fitness and host pressure in shaping hepatitis B diversity"
Institution: The Rockefeller University
Named Award: Berger Foundation Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Charles M. Rice, PhD
Cancer Type: Other Cancer
Research Area: Virology
Jennifer M. Kalish, MD, PhD

Dr. Kalish is studying a rare hereditary syndrome called Beckwith-Wiedemann syndrome (BWS), which increases the risk of children developing kidney and liver cancers. These individuals have epigenetic changes on chromosome 11 that are found in other types of cancers. Epigenetic markers modify DNA so gene expression is turned on or off; changes in this process can cause cancer. By understanding how cancer is triggered in BWS, Dr. Kalish aims to identify pathways that can be targeted for the development of new treatments both for BWS patients and for others with cancers that have similar epigenetic changes. As a physician-scientist, Dr. Kalish established the BWS Registry, which compiles both clinical data and patient samples, and created the first human cell-based models of BWS.

Project title: "Epigenetic and genetic mechanisms of cancer in Beckwith-Wiedemann Syndrome"
Institution: Children's Hospital of Philadelphia
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Marisa S. Bartolomei, PhD, and Garrett M. Brodeur, MD
Cancer Type: Kidney and Bladder, Other Cancer, Pediatric
Research Area: Epigenetics
Tamar Kavlashvili, PhD

Mitochondria harbor independent genetic material known as mitochondrial DNA (mtDNA). This compact, circular molecule encodes proteins essential for the assembly of the mitochondrial electron transport chain to generate energy in form of ATP. Like nuclear DNA, mtDNA is susceptible to damage and mutations. One of the most common disease-causing aberrations of mtDNA is termed “common deletion.” This aberration disrupts mitochondrial function, resulting in neuromuscular diseases and potentially certain cancers, including colorectal cancer. Due to a lack of tools to modify the mitochondrial genome, researchers currently do not understand the mechanisms behind common deletion. Dr. Kavlashvili [Timmerman Traverse Fellow] aims to investigate by using cutting-edge molecular biology tools to edit and visualize mtDNA genomes. She will then be poised to unravel impacts of this deletion on various tissues, in order to ultimately mitigate its pathological impact. Dr. Kavlashvili received her PhD from Vanderbilt University, Nashville and her BS from University of Iowa, Iowa City.

Project title: "Developing Tools to Mechanistically Investigate the mtDNA 'Common Deletion'"
Institution: Memorial Sloan Kettering Cancer Center
Named Award: Timmerman Traverse Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Agnel Sfeir, PhD
Cancer Type: Other Cancer, Colorectal, Skin
Research Area: Cell Biology
Nicholas P. Lesner, PhD

Ammonia, a waste product of cellular activity, is cleared from the body by the liver and kidneys through a process known as the urea cycle. During the urea cycle, ammonia is converted to urea, and arginine (an amino acid) is generated. When liver cells become cancerous, the urea cycle pathway stops functioning and cancer cells must import arginine from outside the cell. When cancer cells are prevented from importing arginine (via removal of arginine from the diet or genetic removal of the transporter), tumors do not grow, suggesting that arginine is critical for cells. However, the function of arginine in the cell is unclear. Using mass spectrometry and mathematical modeling, Dr. Lesner will identify the fate of arginine as it is metabolized by liver cancer cells in mouse models, and investigate how this is altered by various genetic mutations. Additionally, he will examine how restricting arginine from the diet genetically alters the liver and tumor cells. By understanding how disruption of this metabolic pathway influences liver cancer growth in the context of specific cancer drivers, Dr. Lesner aims to inform new therapeutic strategies. Dr. Lesner received his PhD from The University of Texas Southwestern Medical Center, Dallas and his BA from the University of Wooster, Wooster, Ohio.


Project title: "Hepatic urea cycle function in NASH-induced HCC progression"
Institution: University of Pennsylvania
Award Program: Fellow
Sponsor(s) / Mentor(s): M. Celeste Simon, PhD
Cancer Type: Other Cancer
Research Area: Metabolism
Julia Su Zhou Li, PhD

Dr. Li’s research aims to uncover a missing link between repeated DNA sequences, genomic instability, and viruses. While abnormal expansion of “repeats” has been found at unstable genomic regions, known as fragile sites, that are implicated in cancer growth, the mechanisms and consequences of this genomic instability remain poorly understood. Dr. Li recently discovered a cluster of Epstein Barr Virus (EBV)-like repeat sequences in the genome that breaks when bound by abnormally high levels of EBV antigens. These findings illustrate how a chromosome can be broken in long-term EBV infection, which can threaten genome stability and trigger cancer development. Dr. Li aims to leverage this discovery to advance our understanding of how broken repeats threaten genome integrity for clinical screening of individuals susceptible to EBV-associated diseases, and for the prevention and treatment of disease in these individuals. This research could also lead to the discovery of other virus-like repeats and the potential biological function of these virus-like repeats in our genome.  

Project title: “Uncovering the link between repetitive DNA, genomic instability, and tumor viruses”
Institution: University of California, San Diego
Award Program: Dale Frey Scientist
Cancer Type: Blood, Other Cancer, Sarcoma
Research Area: Chromatin Biology
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