Dr. McClune [HHMI Fellow] investigates plant biosynthesis of therapeutic compounds. Approximately half of FDA-approved chemotherapeutics, including first line drugs like paclitaxel (Taxol) and vinblastine (Velban), derive from the arsenal of defensive chemicals that plants synthesize. Unfortunately, both the discovery of new plant-derived therapies and their scalable production are limited by intrinsic challenges of plant biology and genomics. Dr. McClune is developing systematic methods for identifying the biosynthetic pathways plants use to produce defensive molecules. Using single-cell technology, he will characterize rare cells responsible for synthesizing potentially beneficial chemicals and identify the enzymes they use to produce such molecules.

Dr. McGinn studies how bacterial pathogens sense and manipulate their human hosts. Dr. McGinn is focusing on the tick-borne bacterial pathogen Rickettsia parkeri, which can only survive within eukaryotic host cells. By uncovering novel interactions between host and pathogen, his work may reveal new insights into how human cells work and what goes awry in disease states. He is also developing tools to manipulate key virulence pathways in Rickettsia parkeri that can be used to transform the bacteria into a vehicle for delivering antigens or new drugs directly to cancer cells.

Dr. McLaughlin [HHMI Fellow] is using the developing nervous system to study metastasis, the primary cause of cancer-related fatalities. In metastasis, cell surface and secreted molecules enable cells to travel through diverse environments and invade distant tissues. Likewise, growing axons in the developing nervous system use similar sets of cell surface proteins to traverse long distances to form precise connections with their synaptic partner cells. Dr. McLaughlin aims to define the mechanisms used by cell surface proteins to promote axon targeting, which will provide critical insight into how these molecules are harnessed by malignant cells during metastasis. 

Sleep problems may be a risk factor for developing certain types of cancer—lung, colon, pancreas, and breast—and may affect the progression of these cancers and the effectiveness of their treatment. Conversely, symptoms of cancer or side effects of treatment, including restless legs and obstructive sleep apnea, may cause sleeping problems, reducing quality of life. Understanding the complex relationship between cancer and sleep creates opportunities to improve health, treatment options, and quality of life. Specifically, understanding how the peripheral nervous system and the brain regulate both the timing and rhythmicity of sleep (i.e., circadian control), and the balance between time awake and growing sleep pressure (i.e., homeostatic control), could improve survival rates and the quality of cancer treatment. To this end, Dr. Moore [HHMI Fellow] aims to identify the role of circulating dietary cholesterol on sleep and to conduct a targeted genetic screen to identify peripherally secreted proteins that affect either the circadian or the homeostatic control of sleep. These results will provide a means for therapeutic interventions to ameliorate the effects of sleep disruption. Dr. Moore received her PhD from Princeton University and her MS and BS from the City College of New York.

Dr. Niekamp [Dennis and Marsha Dammerman Fellow] studies how gene expression programs are regulated in normal and cancer cells. The ability to switch specific genes "on" and "off" is partly encoded by multiprotein complexes competing for access to target DNA sequences in chromatin structures. The relative distribution of these activating or repressive complexes along chromatin regulates gene expression, and a shift in the balance of these complexes is a hallmark of many cancers. Dr. Niekamp aims to determine how chromatin accessibility is achieved by the competition between activating and repressive complexes, and to understand how well-known cancer mutations disrupt the fine-tuned balance.

As different tissues in the body form, cells need to undergo a complex, precisely timed series of differentiation programs to form specialized cell types. Importantly, premature or delayed initiation of these programs can contribute to cancer formation. However, how timing of cellular differentiation is encoded on a molecular level is poorly understood. Dr. Noetzel is using the protozoan parasite Cryptosporidium parvum as a simplified model of eukaryotic differentiation. After infecting the intestinal lining of a mammalian host, these single-celled parasites undergo exactly three rounds of asexual replication before collectively differentiating into gametes. These studies will investigate how this hard-wired, intrinsic developmental timer is encoded. In his project, Dr. Noetzel aims to understand how these parasites "count to three," which will inform our basic understanding of how eukaryotic cells keep track of time during development. Dr. Noetzel received his PhD from the Weill Cornell Medical College, Cornell University, New York and his MSc and BSc from Georg-August-University, Göttingen.

Dr. Ong [The Mark Foundation for Cancer Research Fellow] is investigating the molecular basis of paraneoplastic syndromes, which occur when a cancer causes unusual symptoms due to hormones produced by the tumor or antibodies produced by the immune system. They can affect the function of various distant tissues and organs in cancer patients, with deadly consequences. Dr. Ong is utilizing a new genetic tumor model in Drosophila that simulates many human paraneoplastic disorders: cachexia, immune dysfunction and early lethality. She aims to uncover how tumor cells impose physiological changes in host tissues at a distance with the hope of uncovering footholds for novel treatments.

Dr. Owens [Suzanne and Bob Wright Fellow] focuses on heat shock proteins (HSPs) and their “master regulator” called heat shock transcription factor 1 (HSF1). The transformation and growth of cancers causes a wide array of cellular stresses including metabolic changes, genomic instability, and protein misfolding that would halt the growth of a normal cell. Tumor cells, however, depend on cellular stress response machinery, like HSPs, for their survival. HSF1 is critical to tumor development and progression, and HSF1 activity is strongly correlated with poor prognosis in many common cancers. For decades, efforts to develop cancer therapies targeting HSPs have failed. Dr. Owens aims to understand how HSPs and HSF1 interact to regulate activity, and how this regulation is co-opted to promote tumor growth and progression.

Oxygen is a double-edged sword in pancreatic cancer biology. Pancreatic cancers require oxygen, but they are amongst the most hypoxic of cancers, with oxygen concentrations as low as 200-fold below atmospheric oxygen concentrations. Pancreatic cancers use oxygen to make molecules critical for their survival and proliferation, but they are also vulnerable to oxidative stress, which is essential for the effectiveness of cancer treatments such as radiation. Dr. Pacold has developed techniques to determine which oxygen-dependent reactions are prioritized by pancreatic cancers and enhanced by radiation treatment, with the goal of identifying new targets that can be used for pancreatic and other cancers that are treated with radiation.

Cancer survivors are at a higher risk of developing blood cancers than the general population due to the toxic effects of cancer treatments. Therapy-related blood cancers are often resistant to existing drugs and therefore extremely challenging to treat. Contrary to previous thought, recent studies show that the mutations causing these blood cancers can be identified in patients' blood many years before they receive therapy. Dr. Papaemmanuil has discovered that the existing mutations alone are not sufficient to cause therapy-related cancer but require the acquisition of additional mutations that affect large segments of the DNA, or "allelic imbalances." She will pursue further studies to screen patients and understand the mechanisms of therapy-related blood cancers. These findings will inform clinical strategies of early detection and targeted intervention to better treat this aggressive disease.