Novel kinase inhibitors in renal cell carcinoma: Progressive development of static agents

Abstract

The rapidly expanding knowledge regarding neoplastic diseases is providing a plethora of new targets for drug discovery and development as exemplified by recent data in renal cell carcinoma. The initial experience with molecularly "targeted" agents has demonstrated that development of the newer non-cytotoxic agents will provide unique challenges requiring modification of many traditional drug development concepts and methods. We discuss recently reported data from a few renal cell carcinoma trials with putative cytostatic agents and highlight issues that need to be addressed for efficient development of cytostatic agents during various phases of clinical development.

Senescence, Necrosis, and Apoptosis Govern Circulating Cell-free DNA Release Kinetics

“…Although senescence is an established form of clonogenic cell death in response to many treatments, including IR, it is possible that some cells interpreted in this study as being senescent may still have been viable and, yet, were not actively contributing to cfDNA release. Many cancer treatments may primarily exert a cytostatic effect, promoting growth arrest without subsequent cfDNA release into circulation (Desai and Stadler, 2006;Martin and Schilder, 2006;Winquist et al, 2006;Ewald et al, 2010). These complexities highlight the need to better understand the relationship between the mechanism of action of a particular treatment and biological responses observed within distinct cell types.…”

PRMT5 as a druggable target for glioblastoma therapy

“…[24][25][26][27][28] An emerging strategy to overcome this therapy resistance is with cytostatic agents that disable the proliferation and growth of the tumor cells and synergize in combination with cytotoxic drugs. [29][30][31] Cellular senescence is a form of persistent cytostatic response by the cells to the stress, wherein cells undergoing senescence cease to proliferate but can remain metabolically active and viable. 32 Therapyinduced senescence is considered an important route to achieving therapeutic sensitivity for tumor cells that are resistant to apoptosis.…”

Systemic Treatments for Metastatic Renal Cell Carcinoma: 10-Year Experience of Immunotherapy and Targeted Therapy

“…However, a clinically relevant increase in CR and OS has not been reported and the role of TT in increasing the curability of mRCC has not been fully elucidated. From a pharmacological viewpoint, the unsatisfactory results of TT to induce a CR may be explained in part by their mechanism of action, which appears to be more cytostatic than cytotoxic [ 15 ]. The current study also showed that the OS (15.8 months), ORR (33.9%), and CR (5.6%) of TT were either similar or inferior to the OS (16.5 months), ORR (31.1%), and CR (10.4%) of IT ( Table 2 ).…”