Research descriptions
Lay description
By studying disease modifier genes we seek to develop new principles to treat cancer, diabetes, autoimmune disorders and cardiovascular disease. Currently most biomedical research focuses on understanding disease pathways. We seek to understand broad-acting disease modifier pathways that determine disease severity, an understudied area from which many useful drugs such as NSAIDs and statins are found. A major thrust of our present work focuses on modifiers of inflammatory processes that contribute significantly and broadly to the severity of age-associated diseases. In our main project, we developed a new class of drugs that, by inhibiting tryptophan catabolism, can recruit the immune system to help chemotherapy and radiotherapy eradicate advanced cancers, including those such as pancreatic cancer that are often refractory to therapy.
In other projects with our Lankenau collaborators, we are developing new agents that target autoimmune disorders, neurodegeneration, and diabetes and obesity-associated complications that promote cardiovascular disease.
Scientific description
Our laboratory is interested primarily in cancer modifier genes, pathogenic inflammation and immunology, and preclinical drug discovery and development that target new principles. We use transgenic mouse models to learn how modifier genes act to drive disease, as well as inform new medicinal strategies to prognose and treat cancer and other age-associated diseases.
Localized cancers are often curable if they are detected before progression to invasive status, but many patients diagnosed with cancer already have invasive disease. What factors dictate malignant progression, and how might they be therapeutically exploited? Molecular therapeutics that target key oncogene and tumor suppressor pathways show some clinical promise, but they have demonstrated limited efficacy to date. Cancer modifier pathways that influence the immune microenvironment of tumor cells may strongly influence clinical course. Indeed, the most exciting area of cancer research today is in immunotherapies that can enable the potential of the patient’s immune system to eradicate advanced cancers. Accordingly, the new therapeutic strategies we have discovered are based on modulating the host immune system to help it clear disease, rather than attacking diseased cells directly.
At LIMR our group has pioneered insights into why tryptophan is so important to cancer cells. A major thrust of this work has been to develop drugs that block IDO and TDO enzymes that consume tryptophan. We have shown how blocking those enzymes can stimulate immune attacks where chemotherapy is ineffective. We have extended the properties of these tryptophan-signaling inhibitors (TSI), part of a larger class of drugs we call immunometabolic adjuvants, through genetic investigations illustrating their significance in the eradication of metastatic cancers.
Our latest studies reveal that TSI can not only stimulate immune attacks but also relieve pathogenic vasculogenesis (blood supply) in metastatic cancers and other diseases characterized by abnormal blood supply (e.g., diabetic retinopathy, age-associated macular degeneration). Lastly, the laboratory is also engaged in studying how the IDO2 enzyme, discovered at LIMR, works to sustain GI cancers and autoimmunity differently from IDO or TDO.
Our RhoB investigations derive from our long-standing leadership in studies of this Ras/Rho family small GTPase in cell stress signaling and pathogenic inflammation. Recent work in collaboration with Drs. Lisa Laury-Kleintop and Laura Mandik-Nayak at Lankenau has illuminated exciting new findings that show how RhoB broadly sustains autoimmune, ocular, metabolic and cardiovascular diseases. In particular, a new therapeutic antibody has been developed to target RhoB, which may be useful to treat a variety of inflammation-related diseases in medicine, including autoimmune disorders, atherosclerosis, diabetes, kidney disease and ocular disorders. In other works emerging from our RhoB studies, we also are developing the medicinal properties of an FDA-approved formulant called meglumine, which we discovered to exert anti-diabetic effects associated with insulin-independent pathways associated with anti-inflammation and increased muscle stamina.
Our Bin1 investigations originating in cancer suppression studies led us to discover that it regulates inflammation and is important for sustaining effective antitumor immunity. Recently, in preclinical studies we found that its genetic blockade can limit the development of inflammatory bowel disease (IBD, including ulcerative colitis and Crohn’s disease). Building on this finding, we have identified a Bin1 antibody that can treat this disorder in a preclinical IBD model. Interestingly, other biomedical laboratories focused on neurodegeneration recently found that Bin1 gene variants that elevate Bin1 protein levels in the brain confer a high risk of late-onset Alzheimer’s disease, second only to ApoE variants in risk. We recently reported evidence that our Bin1 antibody that limits IBD also exhibits therapeutic properties in a preclinical model of Alzheimer’s disease, building on the idea that targeting Bin1 may be effective in limiting onset of this common neurodegenerative disorder.
