Translational medicine is currently the focus of much attention in the medical and research community and is the wave of the foreseeable future. “Translational medicine” is a catchphrase for the attempt to improve communication between basic science and clinical medicine so as to accelerate the development of drugs that attack key targets involved in diseases. This involves a multidisciplinary effort with continuous feedback, collaboration, and data-sharing.
Vast amounts of money are being spent in this effort by the federal government and pharmaceutical companies. The Translational Research Working Group (TRWG) was established to work with the cancer research community to develop recommendations about how the National Cancer Institute could best organize its efforts to further translational research. The TRWG defined a translational continuum and developed a “roadmap” to create a stronger research infrastructure to accelerate the clinical research enterprise. The field has moved forward with its own journal—the Journal of Translational Medicine.
Efforts in translational medicine have paid off in the development of cancer treatments like imatinib (Gleevec) for chronic myeloid leukemia and gastrointestinal stromal tumors (GISTs) and trastuzumab (Herceptin) for HER2/neu
-positive breast cancer. Both imatinib and trastuzumab have in fact revolutionized treatment of these respective cancers and are lifesaving for patients who previously had no good treatment options.
According to researchers, prostate cancer poses a major challenge for those involved in translational medicine, mainly due to its heterogeneity. However, progress is being made on several fronts.
Characterizing Prostate Cancer
According to Robert DiPaola, MD, of The Cancer Institute of New Jersey at Robert Wood Johnson Medical School in New Brunswick, New Jersey, the field of prostate cancer is advancing due to a greater synergy between basic research and clinical science, aided by the discovery of molecular pathways, genetic alterations, mechanisms of drug resistance, and findings based on the clinical effectiveness of specific therapies.
DiPaola reviewed advances in characterization of targets and the pathways that drive prostate cancer in terms of discovering targets for drug development. He also discussed oncogenic targets, such as growth signaling pathways and apoptosis, and said that a more recent focus for drug development is nononcogenic stress response targets.
“Prostate cancer is a heterogeneous disease, making it difficult to personalize treatment,” he said. “The identification of new targets, made possible by sophisticated DNA microarrays from prostate cancer specimens, will move the field forward.” Some new targets include TMPRSS22- ERG, RAF, P13K, RAS/RAF, Rb, and SRC.
Fusions of the androgen-responsive gene TMPRSS22-ERG with transcription factors ERG or ETV1 (both members of the ETS family of transcription factors) have been identified in prostate tumors. Fusions of TMPRSS22-ERG occur in about 50% of invasive cancers, and fusions involving TMPRSS22 with other ETS family proteins occur in an additional 10% of prostate cancers. Genetic rearrangements have been found in 1% to 2% of prostate cancer specimens. In these tumors, DiPaola explained, RAF overexpression seems to be the driving molecular event. This suggests a potential role for small-molecule RAF inhibitors in this subset of patients.
Transcriptome and mutation analysis CNA data have identified P13 kinase (P13K), RAS/RAF, and Rb as oncogenic targets. Overexpression of these genes is predictive of biochemical recurrence following radical prostatectomy.
"The identification of new targets, made possible by sophisticated DNA microarrays from prostate cancer specimens, will move the field forward."
–Robert DiPaola, MD
Based on this research, DiPaola said that there is now a rationale for the combination of targeted therapies in the treatment of prostate cancer. During the past 10 years, there has been a 143% increase in options for treating prostate cancer, and there are now more than 800 agents in clinical development. In general, combination therapies fall into 3 strategies: identification and maximum inhibition of pathways (eg, synthetic lethal screens); inhibition of compensatory pathways; and targeting resistance of “successful” agents.
The hallmarks of targets for cancer therapy have been cell survival, proliferation, and immune evasion. New nononcogenic targets have been identified, including the following new stress phenotypes: mitotic stress, metabolic stress, proteotoxic stress, oxidative stress, and DNA damage stress.