Enhancing Cancer Immunotherapy
For the past 40 years, one of most effective immunotherapies in any malignancy has been the intravesical instillation of bacillus Calmette-Guerin (BCG) for bladder cancer. BCG is an attenuated tuberculoid strain of bacteria that has become a part of the standard of care for patients with bladder cancer. Over the past five years, immune checkpoint inhibitors that target the PD1–PD-L1 axis have been approved for use in bladder cancer, representing the first major therapeutic change in decades. However, although a small fraction of patients show durable therapeutic responses or are cured, the vast majority (over 75 percent) remains unresponsive, highlighting an urgent need to better understand and improve these therapies. The Theodorescu Lab has developed several novel models of murine bladder cancer and is using them to develop approaches that enhance the efficacy of checkpoint inhibitors. Most recently, the lab used an in vivo functional genomic depletion screen and pharmacologic approaches to identify DDR2 as a leading target for the enhancement of response to anti–PD-1 immunotherapy. Current work in the Theodorescu Laboratory aims to identify other molecules like DDR2 that, when inhibited, will enhance checkpoint inhibitors efficacy, while also collaborating with clinical investigators to design clinical trials of combination targeting of DDR2 and PD-1.
Discovery of Tumor and Metastasis Suppressor Genes
Early work in the Theodorescu Laboratory led to the discovery of the first metastasis suppressor, RhoGDI2, using a novel approach of combining gene expression profiling of cell line data with that of clinical tumors. This work was among the first to demonstrate the utility of this approach in finding both mechanistically and clinically relevant genes and has been subsequently used by others. Recently, the Theodorescu Lab used in vivo functional genomic screening to identify several other suppressors of cancer growth, including glycogen debranching enzyme (AGL), which was without a prior known role in cancer. Mechanistic studies of RhoGDI2 and AGL have revealed these genes drive aggressive tumor behavior via convergent pathways, which influenced formulation of new therapeutic approaches targeting endothelin receptor and CD44 in bladder cancer. Clinical trials are being planned for bladder cancer patients at high risk of metastasis development and constitute a prototypical example of translation of bench to bedside research as well as precision oncology. Mechanistic work on defining how these genes work continues.
Novel Approaches to Precision Cancer Medicine
One factor that has driven the Theodorescu Lab’s interest in bladder cancer research is the striking lack of therapeutic options for these patients, especially those with advanced disease, where prognosis is poor. Unlike research in other cancers (breast, prostate, colon, etc.), which have advanced at a much faster pace, improvements in bladder cancer standard of care and overall, as well as progression-free, survival have been marginal. Part of the difficulty in treating bladder cancer with a standard regimen is the high degree of genetic heterogeneity and variable gene expression programs among different bladder tumors. To combat this challenge, the Theodorescu Lab has developed a means of extrapolating therapeutic research on other cancer types to bladder cancer, to effectively look at individual molecular targets expressed in individual bladder tumors and compare their expression profile to other patients with other tumor types containing similar molecular target profiles for which therapeutic response is known. This novel approach led to the development of COXEN (CO-eXpression ExtrapolatioN), a radical strategy based solely on in vitro assays and aimed at personalizing cancer therapy and identifying which new drugs have a high likelihood of being effective. Retrospective studies of COXEN in several tumor types have yielded excellent therapy response prediction in patients. The use of COXEN has also led to the identification of new candidate compounds for the treatment of human bladder cancer. A national SWOG/NCI clinical trial evaluating the ability of COXEN to predict therapy response in bladder cancer has opened and constitutes one of the first precision medicine trials in bladder cancer.
Dan Theodorescu, MD, PhD, began studying the Ras family of GTPases in bladder cancer during his graduate work, and the Theodorescu Laboratory continues down this line of investigation in its current work. The lab has found that the Ral GTPase, a downstream effector of Ras, is a major driver of bladder cancer through a novel mechanism involving CD24 and the androgen receptor. This discovery demonstrated for the first time a mechanism by which the androgen receptor mediates bladder cancer growth and progression. Since there are U.S. Food and Drug Administration–approved therapies to target the androgen receptor, this work has also established the notion of treating bladder tumors with high CD24 expression using androgen receptor blockers. Since Ral also promotes tumor growth via AR/CD24-independent mechanisms, work in the Theodorescu Lab has led to developing agents aimed at Ral inhibition. By targeting the inactive form of Ral through an allosteric site, instead of the common approach of targeting the active site of GTPases, the lab used computational drug-docking algorithms to discover the first targeted agent against Ral GTPase. This agent is now being developed for precision medicine clinical trials by a pharmaceutical collaborator, and the Theodorescu Lab is currently developing optimal drug combinations to use with Ral inhibitors.