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Source: Molecular Cancer Research
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Total 53 results found since Jan 2013.
Abstract B45: c-MYC is a potential therapeutic target for cisplatin-resistant ovarian cancer
Ovarian cancer accounts for approximately 3% of all cancers in women. However, it is the deadliest cancer of the female reproductive system. Due to its non-specific symptoms, ovarian cancer is diagnosed at advanced stages of the disease. The most common standard treatment for advanced ovarian cancer is the platinum-based drugs such as cisplatin. However, over 70% of women relapse due to chemoresistance. Several mechanisms of cisplatin resistance have been described. However, the exact mechanism is not known. Evidence indicates that activation of the transcription factor c-MYC and its regulated genes could be involved in su...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Vivas-Mejia, P. E., Reyes, j., Sood, A. K. Tags: Therapeutic Translation: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B19: MYC induces PLD6 to suppress YAP/TAZ-dependent self-renewal of mammary stem cells
For the maintenance of a given tissue it is absolutely critical to balance proliferation and differentiation of stem cells, progenitor cells and terminally differentiated cells. Perturbations of these finely tuned processes can lead to various diseases such as cancer.One factor that has been implicated in the transition from a stem cell to a progenitor/ transit-amplifying cell is the oncogenic transcription factor MYC. Paradoxically, despite its strong pro-tumorigenic capabilities it has been shown to promote differentiation in several tissues such as the skin or the hematopoietic system.To identify critical pathways that ...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Eyss, B. v., Jaenicke, L. A., Wiese, K., Rosenwald, A., Eilers, M. Tags: Myc Beyond Cancer: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B20: EnCore-LNP mediated tumor delivery of MYC and CTNNB1 Dicer Substrate RNAs (DsiRNAs)
MYC and CTNNB1 are well-characterized drivers of numerous tumor types. Human and preclinical genetic evidence suggest that pharmacological intervention to reduce transactivation of MYC and CTNNB1-regulated genes would yield therapeutic benefit to many cancer patients. Since the proteins encoded by these genes are challenging to target via conventional modalities, progress in new therapeutic agents has been slow despite decades of research. RNA interference technology has enabled the inhibition of previously-undruggable genetic targets at the mRNA level, and has advanced to clinical development for several indications. DCR-...
Source: Molecular Cancer Research - October 18, 2015 Category: Cancer & Oncology Authors: Abrams, M., Ganesh, S., Ying, B., Chopda, G., Saxena, U., Shah, A., Koser, M., Arvan, R., Chen, D., Shui, S., Diwanji, R., Zhou, W., Holmes, B., Kim, B., Yang, H., Patel, M., Cyr, W., Cyr, W., Pursell, N., Avitahl-Curtis, N., Dudek, H., Lai, C., Wang, W., Tags: Therapeutic Translation: Poster Presentations - Proffered Abstracts Source Type: research
NKX3.1-Targeting Kinases
NKX3.1 is a prostate-specific homeodomain protein and tumor suppressor whose expression is reduced in the earliest phases of prostatic neoplasia. NKX3.1 expression is not only diminished by genetic loss and methylation, but the protein itself is a target for accelerated degradation caused by inflammation that is common in the aging prostate gland. NKX3.1 degradation is activated by phosphorylation at C-terminal serine residues that mediate ubiquitination and protein turnover. Because NKX3.1 is haploinsufficient, strategies to increase its protein stability could lead to new therapies. Here, a high-throughput screen was dev...
Source: Molecular Cancer Research - May 12, 2015 Category: Cancer & Oncology Authors: Song, L.-N., Silva, J., Koller, A., Rosenthal, A., Chen, E. I., Gelmann, E. P. Tags: Oncogenes and Tumor Suppressors Source Type: research
Reversal of KRAS-Mediated Apoptosis Resistance
KRAS mutations are frequently detected in human colorectal cancer and contribute to de novo apoptosis resistance and ultimately therapeutic failure. To overcome KRAS-mediated apoptosis resistance, the irreversible proteasome inhibitor, carfilzomib, was evaluated and found to potently induce Noxa, which was dependent upon c-Myc, and Bik. Isogenic mutant versus wild-type KRAS carcinoma cells showed elevated Bcl-xL, confirmed by KRAS siRNA or ectopic expression. Upregulated Bcl-xL by mutant KRAS was mediated by ERK as indicated by ERK knockdown. Bcl-xL expression was regulated at the level of mRNA and protein as shown using a...
Source: Molecular Cancer Research - April 12, 2015 Category: Cancer & Oncology Authors: Okamoto, K., Zaanan, A., Kawakami, H., Huang, S., Sinicrope, F. A. Tags: Cell Death and Survival Source Type: research
Fn14 Regulation of Src-Driven Invasion
The TNF receptor superfamily member Fn14 (TNFRSF12A) is the sole signaling receptor for the proinflammatory cytokine TWEAK (TNFSF12). TWEAK:Fn14 engagement stimulates multiple signal transduction pathways, including the NF-B pathway, and this triggers important cellular processes (e.g., growth, differentiation, migration, and invasion). The TWEAK–Fn14 axis is thought to be a major physiologic mediator of tissue repair after acute injury. Various studies have revealed that Fn14 is highly expressed in many solid tumor types, and that Fn14 signaling may play a role in tumor growth and metastasis. Previously, it was show...
Source: Molecular Cancer Research - March 18, 2015 Category: Cancer & Oncology Authors: Cheng, E., Whitsett, T. G., Tran, N. L., Winkles, J. A. Tags: Signal Transduction Source Type: research
Pol{alpha} and Human Telomeres
This study describes the interplay between DNA replication components with proteins that associate with chromosome ends, and telomerase. These interactions are proposed to be important for the processing and protection of chromosome ends. Mol Cancer Res; 13(3); 402–10. ©2014 AACR.
Source: Molecular Cancer Research - March 18, 2015 Category: Cancer & Oncology Authors: Diotti, R., Kalan, S., Matveyenko, A., Loayza, D. Tags: Cell Cycle and Senescence Source Type: research
ERG Inhibits ANXA2 Expression and Function in Prostate Cancer
Overexpression of ERG in the prostate epithelium, due to chromosomal translocations, contributes to prostate tumorigenesis. Here, genomic analysis of ERG siRNA-treated prostate cells harboring the endogenous TMPRSS2–ERG fusion revealed an inverse relationship between ERG and Annexin A2 (ANXA2) expression at both the RNA and protein level. ANXA2, a Ca2+-dependent and phospholipid-binding protein, is involved in various cellular functions, including maintenance of epithelial cell polarity. Mechanistic studies defined the prostate-specific transcription start site of ANXA2 and showed that the recruitment of ERG to the A...
Source: Molecular Cancer Research - February 19, 2015 Category: Cancer & Oncology Authors: Griner, N. B., Young, D., Chaudhary, P., Mohamed, A. A., Huang, W., Chen, Y., Sreenath, T., Dobi, A., Petrovics, G., Vishwanatha, J. K., Sesterhenn, I. A., Srivastava, S., Tan, S.-H. Tags: Signal Transduction Source Type: research
Abstract PR06: Impact of RAL signal transduction on genetic program and growth control in KRAS- and BRAF-mutated colorectal cells and prognostic potential of pathway-responsive genes in cancer patients
In conclusion, the RALA pathway impinges on the transcription of a distinct subset of target genes in colorectal cancer cells independent of the KRAS and BRAF mutational status. RALA pathway-responsive genes were unaffected by RAF/MAPK and PI3K signaling. These findings support the concept of a pathway-sensitive modular organization of the transcriptome. In view of the correlation of RAL pathway-responsive genes and patient survival, further investigations of the diagnostic impact in prospective trials and exploitation of therapeutic approaches are warranted.This abstract is also presented as Poster B32.Citation Format: Ba...
Source: Molecular Cancer Research - February 5, 2015 Category: Cancer & Oncology Authors: Gyorffy, B., Stelniec-Klotz, I., Sigler, C., Szijarto, A., Qian, Y., Schafer, R. Tags: RAS Biology - Systems Approaches: Oral Presentations - Proffered Abstracts Source Type: research
Abstract A07: Novel effectors of K-Ras-mediated and KSR1 dependent colon tumorigenesis
Conclusion: These results demonstrate the importance of AMPK and its downstream signaling effectors PGC1β and ERRα in maintaining colon tumor cell survival driven by oncogenic Ras and demonstrate the value of using KSR1 as a reference standard to detect genes essential to colon tumor survival.Citation Format: Binita Das, Kurt Fisher, Hyunseok Kim, Deanna J. Volle, Deandra R. Smith, Robert S. Livergood, John MacMillan, Michael White, Robert Lewis. Novel effectors of K-Ras-mediated and KSR1 dependent colon tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to T...
Source: Molecular Cancer Research - February 5, 2015 Category: Cancer & Oncology Authors: Das, B., Fisher, K., Kim, H., Volle, D. J., Smith, D. R., Livergood, R. S., MacMillan, J., White, M., Lewis, R. Tags: RAS Effectors - Basic Biology: Poster Presentations - Proffered Abstracts Source Type: research
Abstract IA15: Membrane targeting of Ras
Ras proteins are targeted to membranes by virtue of post-translational modifications of their C-terminal hypervariable regions (HVRs). Because Ras proteins signal only when associated with cellular membranes, the Ras trafficking pathway is considered an attractive area for anti-cancer drug discovery. The three mammalian Ras genes, hras, nras and kras, give rise to four Ras proteins because the transcript of the kras locus is alternatively spliced to encode K-Ras4A and K-Ras4B. The kras locus is most often mutated in human cancer and when mutated gives rise to oncogenic forms of both K-Ras4A and K-Ras4B. The four Ras protei...
Source: Molecular Cancer Research - February 5, 2015 Category: Cancer & Oncology Authors: Tsai, F., Fehernbacher, N., Sung, P., Court, H., Philips, M. R. Tags: RAS Regulation: Oral Presentations - Invited Abstracts Source Type: research
Abstract B36: Targeting oncogenic RAS with small molecule PKC-delta inhibitors
We report here that PKC-delta inhibition is cytotoxic in melanomas with primary NRAS mutations. Novel small-molecule inhibitors of PKC-delta were designed as chimeric hybrids of two naturally-occurring PKC-delta inhibitors, staurosporine and rottlerin. The specific hypothesis we have interrogated and validated is the concept that combining two domains of two naturally-occurring PKC-delta inhibitors into a chimeric or hybrid structure retains biochemical and biological activity, and improves selectivity for the specific PKC-delta isozyme. We have devised a potentially general synthetic protocol to make these chimeric specie...
Source: Molecular Cancer Research - February 5, 2015 Category: Cancer & Oncology Authors: Takashima, A., Chen, Z., English, B., Williams, R. M., Faller, D. V. Tags: RAS Targeting: Poster Presentations - Proffered Abstracts Source Type: research
Abstract A40: Targeting TBK1 promotes apoptosis in MEK-inhibitor resistant mutant NRAS melanoma cells
Melanoma is a devastating form of skin cancer. Fifteen to twenty percent of melanoma patients have an activating mutation in the GTPase, NRAS. Despite advances in the targeted inhibitor treatment for mutant BRAF melanoma patients, the options for mutant NRAS patients remain poor. TANK-binding kinase 1 (TBK1) is an atypical IB kinase family member that acts downstream of the RAS effector RalGEF but the role of TBK1 in melanoma is not known. We found that NRAS overexpression in wild-type NRAS melanoma cells increased TBK1 phosphorylation. In a panel of NRAS mutant melanoma cells, we characterized sensitivity to MEK inhibitio...
Source: Molecular Cancer Research - February 5, 2015 Category: Cancer & Oncology Authors: Vu, H. L., Aplin, A. E. Tags: RAS Effectors - Therapeutics: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B47: Therapeutic KRAS silencing in lung and colon cancer models
This study highlights the potential translational impact of therapeutic RNA interference, which may have broad applications in oncology, especially for traditional "undruggable" targets.Citation Format: Chad Pecot, Sherry Wu, Seth Bellister, Rajat Bhattacharya, Anshumaan Maharaj, Cristian Rodriguez-Aguayo, Vianey Gonzalez-Villasana, Rajesha Rupaimoole, Gabriel Lopez-Berestein, Lee M. Ellis, Anil Sood. Therapeutic KRAS silencing in lung and colon cancer models. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR;...
Source: Molecular Cancer Research - February 5, 2015 Category: Cancer & Oncology Authors: Pecot, C., Wu, S., Bellister, S., Bhattacharya, R., Maharaj, A., Rodriguez-Aguayo, C., Gonzalez-Villasana, V., Rupaimoole, R., Lopez-Berestein, G., Ellis, L. M., Sood, A. Tags: RAS Targeting: Poster Presentations - Proffered Abstracts Source Type: research
Abstract B48: Regulation of mutant KRAS protein stability via SMURF2:UBCH5 complex mediated degradation of beta-TrCP1
Attempts to target mutant KRAS have been unsuccessful. Most of the current therapeutic approaches are indirect, mainly via inhibiting KRAS down-stream signaling, which have been marginally successful. Here we report the identification of Smad ubiquitination regulatory factor 2 (SMURF2), a HECT-type ubiquitin ligase (E3) as a critical regulator of mutant KRAS protein stability. We show that the loss of SMURF2 either by si-/sh-RNA mediated gene silencing or by overexpression of a catalytically inactive SMURF2 Cys716Ala (CA) mutant, can cause lysosome-mediated KRAS degradation; whereas, overexpression of wild type SMURF2 enha...
Source: Molecular Cancer Research - February 5, 2015 Category: Cancer & Oncology Authors: Shukla, S., Allam, U. S., Ahsan, A., Chen, G., Beer, D. G., Lawrence, T. S., Nyati, M. K., Ray, D. Tags: RAS Targeting: Poster Presentations - Proffered Abstracts Source Type: research
