Dr. Costa is studying how cells interact with one another through cell-surface adhesion molecules. During cancer progression, cancer cells can change expression of some of these molecules to metastasize and evade the immune system. Dr. Costa is using the parasite Toxoplasma gondii, which can recognize and invade nearly all mammalian cells, to uncover novel proteins involved in this recognition. By characterizing the specificity of these interactions for different host cells, she hopes to expand the ability to recognize and mark specific cells, which could be harnessed for cancer diagnostics and therapeutic intervention.

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. 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.

We share our bodies with trillions of microorganisms: the microbiota. The microbiota interacts with our bodies to affect health and disease, including cancer development and response to therapies. For example, in patients receiving hematopoietic stem cell transplantation as treatment for leukemias, lymphomas, and other blood cancers, disruptions in the microbiota have been linked to disease relapse, infections, treatment complications, and survival. Given these serious effects, it is important to understand how to manipulate the microbiota through therapies like prebiotics: carbohydrates that can be ingested to stimulate the growth and maintenance of various bacteria. The challenge is that different people have different microbiotas and therefore may respond differently to the same prebiotic. To address this challenge, Drs. David and Sung have developed a novel microfluidic platform to isolate individual bacteria from a patient’s stool sample and grow them against selected prebiotics, allowing an understanding of how a given patient’s microbiota may respond to different prebiotics. To do this using conventional techniques would take a stack of petri dishes as tall as the Empire State Building and months of work; their innovative system can do it in a single day. They believe that by using this novel system, they will be able to predict the best prebiotic for a given patient, thereby manipulating their microbiota and improving cancer outcomes. They will test this strategy using patient samples in their artificial gut “bioreactor” as well as in mouse models. The success of this project would lead to clinical trials of personalized prebiotics.

Dr. Dixon aims to determine whether the altered metabolism of cancer cells creates new vulnerabilities that can exploited therapeutically. “Reductive stress” is a cellular concept in which too much glutathione could lead to cell growth arrest and death. He is investigating how a gene called NRF2 balances the demand for new glutathione synthesis with the need to avoid glutathione-mediated reductive stress. Reductive stress-mediated protein unfolding and aggregation may burden the protein folding and stress response machineries and explain, in part, the heightened sensitivity of cancer cells to inhibitors of these pathways. Thus, his work could also suggest new approaches to selectively eliminate cancers with mutations that lead to high NRF2 expression, using agents that enhance reductive stress. His central goal is to characterize cell-specific metabolic alterations and seek new ways to exploit these differences therapeutically.

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. Eichel is studying how proteins travel across cellular membranes and are sorted to different areas of the cell. This highly regulated mechanism generates distinct membrane domains of the cell with unique protein compositions, which are essential for cellular functions. Dr. Eichel hopes to understand how membrane trafficking plays a role in cancer biology, including loss of cellular polarization, uncontrolled cell growth, invasion, and metastasis.

Cancer therapies that target a specific gene product (targeted therapies), for example the oncogenic BCR-ABL by Gleevec, are now a very successful paradigm in cancer treatment. However, many known cancer-driving proteins are recalcitrant to the development of traditional small molecule inhibitors. In recent years, novel pharmacologic strategies have been proposed and developed to tackle this pervasive problem in drug development. One such novel pharmacologic modality is called “degraders,” small molecules that hijack the cellular waste disposal system – the ubiquitin proteasome system – to remove a cancer-causing protein from the cell. While the concept has shown incredible success in the case of lenalidomide (Revlimid) for the treatment for 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 for the mechanism of action of degraders, and further develop a novel class of small molecule degraders to target oncogenic gene products. He anticipates that this work will contribute to the development of novel medicines for 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.