Our Science – Fojo Website
Antonio Tito Fojo, M.D., Ph.D.
Nearly everyone agrees that drug resistance is a major impediment to effective chemotherapy. Indeed, it could be argued that our problem is not that we lack effective agents, since nearly all agents in common use can cure a variety of cancers, but instead that some cancers are more resistant. An extension of this thesis is the prediction that resistance will be an obstacle all future chemotherapeutic agents will have to overcome. To that end, efforts spent understanding drug resistance now are likely to reap long-term benefits. The available evidence suggests that resistance can be simple or complex but, more importantly, understandable. Clinical evidence suggests that it is also surmountable. High-dose chemotherapy with or without stem cell support represents the most common clinical approach to reverse drug resistance. However, it could be argued that this represents a very nonspecific approach, and that the toxicity of this approach could be lessened, and its efficacy improved, if drug resistance were better understood. The efficacy of high-dose chemotherapy in a subset of malignancies simply demonstrates that resistance is almost never absolute, an observation supported by laboratory studies that show that higher doses overcome all mechanisms of resistance. However, higher doses in patients invariably are associated with and limited by toxicity. Specific therapy designed to interfere with resistance mechanisms should help overcome this obstacle. Based on this, our laboratory efforts have concentrated on the identification of mechanisms of resistance and, equally important, understanding how resistance is acquired. In our opinion, the ultimate goal is not to reverse resistance, but to prevent it from emerging. Our emphasis is on both understanding the basic science and productively conducting translational research. Our clinical efforts emphasize trials that help us better understand drug resistance and that may work in patient with tumors that are refractory to therapy.
In our laboratory, our efforts began with studies of multidrug resistance mediated by P-glycoprotein, which is encoded by the MDR-1 gene. We continue to strive to understand mechanisms of drug resistance that are likely to be clinically relevant, and increasingly are using clinical data to better understand this phenomenon.
The study of drug resistance brought us also to the study of agents targeting microtubules, and we have developed extensive expertise in this field. Our work has now established a paradigm for how these agents work in humans that sets aside sixty years of thinking. Rather than targeting mitosis, we fell that the mechanism of drug action for this class of drugs is interfering with interphase microtubules function and our efforts are currently focused on identifying the critical proteins whose trafficking is interrupted leading to cancer cell death. This novel paradigm not only helps us now better understand drugs we have used clinically for over sixty years, but also opens the possibility of identifying novel targets that may lead us to better therapies.
Finally both clinically and in the laboratory we focus extensively on endocrine cancers, with an emphasis on adrenocortical cancer and malignant pheochromocytoma. We strive to better understand the diseases and are dedicated to identifying ways to better treat these cancers, looking to both improve existing therapies including surgery, as well as identifying novel therapies for patients with advanced disease.
This page was last updated on 6/28/2014.