Dr. Crickard [The Mark Foundation for Cancer Research Fellow] is using high-throughput single molecule imaging to rebuild and visualize the process of homologous recombination (HR) in real time. DNA is subjected to many insults leading to damage. This DNA damage leads to a loss in genomic integrity, resulting in the formation and metastasis of many types of cancer. To guard against DNA damage, cells have developed several complex regulatory networks devoted to repair of damaged DNA, including HR. HR involves the search and pairing of one damaged piece of DNA to similar or identical DNA sequences to promote repair of the damaged piece, thus maintaining genome integrity. He seeks to understand, at the most basic biochemical level, how two of the key protein components in HR, Rad51 and Rad54, function to find and repair damaged DNA. His findings will give new insights into how cells fix damaged DNA, which may be key to the development of novel treatments and therapeutic options for all types of cancer.

Dr. Crossley is developing reaction-based chemistry to address the problem of “undruggable” targets in cancer therapy. These proteins lack grooves or “pockets” on the surface that can potentially bind small molecule drugs. A small molecule that can react with an amino acid in the target protein, forming a covalent bond, may circumvent the problem of poor binding pockets. Dr. Crossley aims to find drugs that will target the most problematic cancer-causing proteins, expanding the potential to treat cancers that currently have few therapeutic options.

Dr. Dann is studying how the addition of the amino acid arginine to proteins regulates their biological activity. When this process malfunctions, cancerous genes are transcribed into proteins. Dr. Dann will use high-resolution mass spectrometry to identify arginine-modified proteins in cells, chemical biological tools to decipher the role of such modification in determining protein function, and functional genomics to understand how this process regulates the genome.

Dr. Dodson is investigating how defects that are not strictly based on DNA mutations can be passed from parent to progeny for multiple generations. Germ cells, the producers of eggs and sperm in animals, normally transmit the blueprint for life from parent to progeny. When germ cells acquire defects, however, these defects may also pass from parent to progeny. These underexplored defects may contribute to the onset and inheritance of familial cancer syndromes, and a better understanding of them could result in new cancer therapies.

Dr. Dumesic seeks to understand how physical exercise promotes health. In addition to strengthening skeletal muscle, exercise also benefits distant organ systems, providing protection from metabolic disorders and chronic diseases including cancer. These widespread effects highlight muscle’s ability to communicate via secreted signals. However, the ability to pharmacologically modulate these signals for therapeutic gain is challenged by our limited understanding of their identities and mechanisms of action.  By identifying muscle-derived signaling factors involved in muscle homeostasis and systemic metabolism, this research promises to suggest new avenues for therapy against cancer-associated cachexia, a condition of muscle wasting and perturbed metabolism.

Dr. Einav is focusing on how the human immune system, with its millions of different antibodies, protects us against a range of assaults from pathogens such as influenza to rapidly evolving cancers. Recently, researchers have designed antibodies to help the body fight cancer, infection and other diseases. These efforts have only begun to tap into the potential of developing antibody mixtures. By understanding the collective action of multiple antibodies, this research will investigate how the immune repertoire can be bolstered to better combat diseases.

Dr. Ellison is investigating how single bacterial cells join together to form complex, multicellular structures called biofilms. Biofilms protect bacterial cells from antibiotics and antimicrobial agents, making them difficult to eliminate. Some biofilm-forming species may cause certain cancers, and biofilms of infectious bacteria threaten immunocompromised patients such as those undergoing chemotherapy. Dr. Ellison focuses on bacterial appendages called type IV pili that play a crucial role in biofilm formation. Understanding the role of pili and their contribution to biofilm progression may lead to novel therapies to eliminate biofilms. 

Targeted cancer therapies that interfere with specific molecules involved in the growth, progression and spread of cancer have been successful in cancer treatment in recent years. However, many known cancer-driving proteins are recalcitrant to the development of traditional small molecule inhibitors.  To address this problem in drug development, researchers are developing "degraders," small molecules that direct cancer-causing proteins to the cellular waste disposal system - the ubiquitin proteasome system - to eliminate them from the cell. While the concept has shown incredible success in the case of lenalidomide (Revlimid) for treating multiple myeloma, our understanding of the underlying mechanism is insufficient to broadly apply degraders to cancer treatment. Dr. Fischer's research will expand our molecular understanding of how degraders work and develop a novel class of small molecule degraders to target oncogenic gene products. His work will likely contribute to new approaches to treat many cancers.

Over 90% of cancer deaths are caused by metastasis, the spread of cancer cells to distant organs, where uncontrolled cancer cell growth lethally compromises organ function. Despite recent advances, current treatments fail to effectively control metastasis. Dr. Ganesh is growing colorectal cancer cells, removed from patients during surgery, as three-dimensional “organoids.” This cutting-edge technology models the complexity of human organs more accurately than cells growing in a dish. Using colorectal cancer organoids, her group is studying how cancer cells gain the ability to spread and grow outside their organ of origin. Her work is uncovering core signaling modules required for metastasis, with the goal of developing more effective treatments for patients with advanced cancers. Dr. Ganesh works under the mentorship of Joan Massague, PhD, at Memorial Sloan Kettering Cancer Center, New York.

Dr. Gao aims to understand the mechanism that proteins inside the cell use to enter peroxisomes. Peroxisomes are organelles that play important roles in fatty acid degradation, ether-phospholipid biosynthesis, and breakdown of hydrogen peroxide. Mutations in genes that cause faulty peroxisome function, particularly those that affect matrix protein import, result in a variety of severe inherited human diseases referred to as peroxisome biogenesis disorders (PBD). Cancer cell lines also strongly depend on peroxisomes for survival, which suggests that pharmacologic targeting of peroxisomes could be a novel cancer therapy. Dr. Gao is using a combination of biochemical and biophysical approaches to investigate the peroxisomal import machinery with the goal of deciphering its mechanism and developing better cancer therapies.