Article - Targeting the RB-Pathway in Cancer Thera

Article - Targeting the RB-Pathway in Cancer Therapy

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Abstract

The RB-pathway, consisting of inhibitors and activators of cyclin-dependent kinases, the retinoblastoma tumor suppressor (RB), and the E2F-family of transcription factors, plays critical roles in the regulation of cell cycle progression and cell death. Components of this pathway, particularly p16Ink4a, cyclin D1, and RB, are frequently altered in sporadic human cancers to promote deregulated cellular proliferation. The consistent disruption of the RB-pathway in human cancers raises the possibility of exploiting tumor-specific RB-pathway defects to improve the efficacy of current therapies and to develop new therapeutic strategies. This chapter discusses how the RB-pathway status impacts the cellular responses to cytotoxic, cytostatic and hormone therapies, and how the components of the RB-pathway may be directly targeted to treat cancer.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822892/

Poster - American Association for Cancer Research (AACR) Annual Meeting: “Kevetrin Targets Both MDM2-p53 and Rb-E2F Pathways in Tumor Suppression”

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Conclusion

Due to the complexity of pro-apoptotic and anti-apoptotic pathways with multiple players involved and redundant signaling networks, blocking only one anti-apoptotic factor may not result in antitumor activity. However, Kevetrin acts via multiple targets to produce efficacy in a wide range of xenograft tumor models.

Kevetrin has potent antitumor activity in several wild type and mutant p53 human tumor xenografts, e.g., A549, MIA Paca-2, MDA-MB-231, K-562, PC3, HT-29, NCI-H1975, HCT-15 and LNCaP. Kevetrin modulated the expression of HDAC2 and HDAC6. HDAC inhibition/regulation has been shown to mediate cell death through several pathways, including cell cycle arrest, induction of apoptosis, anti-angiogenesis and affects misfolded protein response pathways. Kevetrin acts through alterations in chromatin modification and gene expression, modification of the expression and function of the HDAC6-chaperone axis and modulation of transcription factor expression. Kevetrin induced apoptosis by upregulation of pro-apoptotic protein expression and downregulation of anti-apoptotic proteins in different cell lines. Kevetrin induced cell cycle arrest via induction of p21 in many p53 wild type, mutant and null cell lines.

In recent years, HDAC has emerged as a promising target for therapeutic interventions that could revert the aberrant epigenetic states associated with cancer. Overexpression of HDAC1 and HDAC2 have been reported in many types of cancer. Downregulation of HDAC2 by Kevetrin induced upregulation of specific pro-apoptotic genes and/or downregulation of prosurvival genes, therefore reactivating pathways controlling apoptosis or cell growth.

Rb-E2F and MDM2 p53 pathways are crucial regulators of cell cycle progression. E2F1 overexpression, observed in most tumors, is associated with tumor growth. Kevetrin downregulated E2F1 and its target gene, thymidylate synthase, in A549, MIA PaCa-2, K-562, and NCI-H1975 cell lines. In xenograft models with these tumors, Kevetrin had very potent anti-tumor activity. Transcription factor p53 is a major tumor suppressor and its stability determines whether it has the capacity to carry out its task. MDM2 is the E3 ubiquitin ligase that promotes ubiquitin-dependent proteosomal degradation of p53. Kevetrin activates and stabilizes the wild type p53 by monoubiquitination. Stable monoubiquitinated p53 accumulation in cytosol or mitochondria directly activates apoptosis. Kevetrin degrades mutant p53 in MDA-MB-231 and other mutant cell lines. Degradation of mutant p53 by Kevetrin can chemosensitize mutant p53 cancer cells to chemotherapeutic drugs. Kevetrin acting through both major pathways of tumor suppression, Rb-E2F and MDM2-p53, has far reaching consequences.

Kevetrin’s multi-targeted mechanism likely contributes to its potent anti-tumor activity in various tumor types with varied p53 mutation status. This unique selectivity in turn supports Kevetrin’s low toxicity profile observed during GLP safety pharmacology and toxicity studies. We plan to initiate a Phase I clinical trial at Dana-Farber/Harvard Cancer Centers in 2012.

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