The diverse expression patterns of the tumor suppressor p53 in cancer cells reflect the regulatory efficiency of multiple cellular pathways. By contrast, many human tumors are reported to develop in the presence of wild-type p53. Recently, several oncogene inhibitors have been used clinically to suppress tumor development by functionally reactivating other oncoproteins. On the other hand, p53 reactivation therapies have not been well established, as few of the p53-MDM2 complex inhibitors such as Nutlin-3 induces mutation in p53 gene upon prolonged usage. Therefore, in this study CopA3, a 9-mer dimeric D-type peptide with anticancer activity against the human colorectal cancer cells, was used to explore the efficacy of p53 reactivation in-vitro and in-vivo. The anticancer activity of CopA3 was more selective towards the wild-type p53 expressing cells than the p53 deficient or mutant colorectal cancer cells. In response to this, this study investigated the signaling pathway in vitro and validated its anti-tumor activity in-vivo. The protein-peptide interaction and molecular docking efficiently provided insight into the specific binding affinity of CopA3 to the p53-binding pocket of the MDM2 protein, which efficiently blocked the p53 and MDM2 interaction. CopA3 plays a crucial role in the binding with MDM2 and enhanced the nuclear translocation of the p53 protein, which sequentially activated the downstream targets to trigger the autophagic mediated cell death machinery through the JNK/Beclin-1 mediated pathway. Collectively, CopA3 affected the MDM2-p53 interaction, which suppressed tumor development. This study may provide a novel inhibitor candidate for the MDM2-p53 complex, which could ultimately suppress the growth of colorectal cancer cells without being cytotoxic to the healthy neighboring cells present around the tumor microenvironment.

01 Jan 2016·Молекулярная биология

Гипотетические SNP-маркеры, значимо изменяющие оценки сродства тата-связывающего белка к промоторам онкогеновVEGFA,ERBB2,IGF1R,FLT1,KDRиMET –мишеней для химиотерапии

Article

Author: Kolchanov, N A ; Ponomarenko, P M ; Ponomarenko, M P ; Rasskazov, D A ; Savinkova, L K ; Arkova, O V ; Turnaev, I I

The following hypothesis has been proposed: IF an SNP can significantly increase the expression of an oncogene by increasing the affinity of the TATA-binding protein (TBP) to its promoter, THEN this SNP can also reduce the apparent bioactivity of inhibitors of this oncogene during antitumor chemotherapy and vice versa. In the context of this hypothesis, the previously proposed method (http://beehive.bionet.nsc. ru/cgi-bin/mgs/tatascan/start.pl) was applied to analyze all SNPs found within the [-70; -20] regions (which harbor all proven TBP-binding sites) of the promoters of VEGFA, EGFR, ERBB2, IGF1R, FLT1, KDR, and MET oncogenes according to the human reference genome, hg19. For 83% of these SNPs, their effect on TBP affinity to the oncogene promoters required for assembly of preinitiation complexes was not significant. rs36208385, rs36208384, rs370995111, rs372731987, rs111811434, rs369547510, rs76407893, rs369728300, and rs72001900 can potentially serve as SNP markers to reduce the apparent bioactivity of oncogene inhibitors, while rs141092704, rs184083669, rs145139616, rs200697953, rs187746433, rs199730913, rs377370642, rs114484350, rs374921120, rs146790957, rs376727645, and rs72001900 can be the markers for enhancing this activity.

01 Jan 2015·Cancer Immunology ResearchQ1 · MEDICINE

Type I Cytokines Synergize with Oncogene Inhibition to Induce Tumor Growth Arrest

Q1 · MEDICINE

Article

Author: Stroncek, David F. ; Raffeld, Mark ; Hanada, Ken-ichi ; Liu, Hui ; Roychoudhuri, Rahul ; Mehta, Gautam U. ; Clever, David ; Goldlust, Ian S. ; Xi, Liqiang ; Pflicke, Holger ; Wang, Ena ; Klebanoff, Christopher A. ; Lee, Chyi-Chia R. ; Ji, Yun ; Palmer, Douglas C. ; Bosenberg, Marcus W. ; Sukumar, Madhusudhanan ; Morrow, James J. ; Roelke-Parker, Melody ; Gros, Alena ; Franco, Zulmarie ; Gattinoni, Luca ; Marincola, Francesco ; Restifo, Nicholas P. ; Acquavella, Nicolas ; Yu, Zhiya ; Crompton, Joseph G.

AbstractBoth targeted inhibition of oncogenic driver mutations and immune-based therapies show efficacy in treatment of patients with metastatic cancer, but responses can be either short lived or incompletely effective. Oncogene inhibition can augment the efficacy of immune-based therapy, but mechanisms by which these two interventions might cooperate are incompletely resolved. Using a novel transplantable BRAFV600E-mutant murine melanoma model (SB-3123), we explored potential mechanisms of synergy between the selective BRAFV600E inhibitor vemurafenib and adoptive cell transfer (ACT)–based immunotherapy. We found that vemurafenib cooperated with ACT to delay melanoma progression without significantly affecting tumor infiltration or effector function of endogenous or adoptively transferred CD8+ T cells, as previously observed. Instead, we found that the T-cell cytokines IFNγ and TNFα synergized with vemurafenib to induce cell-cycle arrest of tumor cells in vitro. This combinatorial effect was recapitulated in human melanoma–derived cell lines and was restricted to cancers bearing a BRAFV600E mutation. Molecular profiling of treated SB-3123 indicated that the provision of vemurafenib promoted the sensitization of SB-3123 to the antiproliferative effects of T-cell effector cytokines. The unexpected finding that immune cytokines synergize with oncogene inhibitors to induce growth arrest has major implications for understanding cancer biology at the intersection of oncogenic and immune signaling and provides a basis for design of combinatorial therapeutic approaches for patients with metastatic cancer. Cancer Immunol Res; 3(1); 37–47. ©2014 AACR.See related commentary by Riddell, p. 23

100 Deals associated with Oncogene Targets (Codiak BioSciences)

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Indication	Highest Phase	Country/Location	Organization	Date
Hematologic Neoplasms	Preclinical	US	Codiak BioSciences, Inc.	20 Apr 2022
Solid tumor	Preclinical	US	Codiak BioSciences, Inc.	20 Apr 2022

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