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Renal Cell Carcinoma: New Developments in Molecular Biology and Potential for Targeted Therapies
Personalised recommendations. Cite protocol How to cite? Entrance of proteins into the 20S core is sterically inhibited in the absence of a 19S regulatory particle, which consists of a multisubunit proteasome lid and base. Proteins destined for degradation are targeted by specific phosphorylations and subsequently recognized by E3-ubiquitin ligase complexes that add polyubiquitin chains. The polyubiquitylated proteins are bound by the proteasome lid and threaded into the 20S core where they are hydrolyzed.
Furthermore, the presence a wild-type VHL gene appears to sensitize RCCs to the antitumor effects of bortezomib [ 93 ]. As expected, neuropathy was the most significant toxicity seen [ 94 , 95 ]. Histone deacetylation makes DNA more compact and prevents access of transcription factors stopping gene expression. In fact, many transcription regulators act in part by recruiting histone deacetylases HDACs. Inevitably, phase II trials with limited accrual are the first and necessary steps to demonstrate clinical efficacy of a new anticancer drug.
In the absence of a comparative group, efficacy is mainly judged on response rates following Response Evaluation Criteria in Solid Tumors [ 99 ]. A frequently adopted alternative trial design involves randomized discontinuation, intended to identify whether disease stabilization can be attributed to the study treatment. Although such a design often provides valuable information, it has the inconvenience of requiring accrual of a larger number of patients than a typical phase II trial. Moreover, many patients refuse inclusion for not accepting the possibility of having to discontinue an active treatment.
A possible evolution in trial design for biological agents may come with the development of new assessment systems imaging and biomarkers for disease activity, moving away from strict size parameters. Several new drugs have been approved recently for the treatment of advanced RCC, and many other compounds are undergoing preclinical or early clinical experimentation Table 1.
However, except for some patients treated with high-dose IL-2, current treatments have improved quality of life, delayed progression, and extended survival, but have not increased the cure rate for RCC. One approach has been to bring the advances obtained in the metastatic setting earlier in the course of disease following the paradigm established in breast, colorectal, and lung cancer, where the administration of active agents shortly after primary tumor resection in high-risk patients prevents relapse and saves lives. In this regard, a large ongoing intergroup trial Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma involves the randomization of high-risk patients who have undergone nephrectomy to receive placebo, sorafenib, or sunitinib for 1 year.
Two other international adjuvant studies, the STAR sunitinib trial in advanced renal cancer and the SORCE a phase III randomized, double-blind study comparing sorafenib with placebo in patients with resected renal cell carcinoma at high or intermediate risk of relapse trials, will address the benefit of adjuvant sunitinib and sorafenib, respectively. Another innovative approach currently being tested is the use of neoadjuvant therapy to increase the resectability of large primary tumors. In almost every example in oncology, curative chemotherapy consists of a combination of two or more agents having different mechanisms of action and minimally overlapping toxicities.
Therefore, improvements in the treatment of advanced RCC are likely to originate from combination of existing drugs, as well as the development of new compounds. In general, targeted agents have fewer side effects than traditional chemotherapeutic agents, which in principle should make them more amenable to combination. Concomitant use of more than one compound may allow interruption of an important cancer pathway at more than one point e.
We believe this approach holds more promise than the sequential use of monotherapy because crossresistance between agents is expected and all the RCC agents have very limited durations of benefit. Some combinations currently being tested are bevacizumab plus sunitinib, sorafenib plus everolimus, sirolimus plus erlotinib, and vorinostat plus bevacizumab, among others.
Metastatic RCC is a relatively uncommon malignant disease with a dismal outcome, and improvements will be accomplished only by a concerted effort to include patients in clinical trials that are rational and well designed. Ideally, to be most effective, future trials should provide biologic information on why they succeeded or, alternatively, why they failed. User Name Password Sign In.
Drabkin, M. Received August 8, Accepted October 8, Previous Section Next Section. View this table: In this window In a new window.
Molecular biology and targeted therapies for urothelial carcinoma.
Table 1. Summary of toxicity and efficacy of RCC agents. Nephrectomy Contrary to what has been the paradigm in many other solid tumors, nephrectomy is often performed in RCC even with evidence of metastatic disease. Stem Cell Transplantation There have been attempts to achieve graft-versus-tumor effects using nonmyeloablative, allogeneic stem cell transplantation. Multikinase Inhibitors Small-molecule kinase inhibitors that have more than one target multikinase inhibitors are generating considerable excitement in the treatment of metastatic RCC.
Proteosome Inhibitors The proteosome is a 26S barrel-shaped structure with internally located proteases. Previous Section.
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Investigational chemotherapies for pancreatic cancer
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- The relationship between cell signaling and cancer.
- Targeted Therapies: A New Generation of Cancer Treatments.
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