Drug Combination Shows Benefit in RAS-Driven Cancers

Excerpt:

“Cancers driven by the RAS oncogene are aggressive and difficult to treat, and thus far precision drugs haven’t been able to target the mutant RAS gene successfully.

“But in a presentation at the American Association for Cancer Research Annual Meeting on Monday, April 3, 2017 at 10:30 a.m., in Washington DC, Dana-Farber Cancer Institute scientists said a number of in a small study with RAS-driven lung, ovarian, and thyroid cancers got long-term clinical benefit from a combination of two drugs that targeted molecular pathways controlled by the RAS gene.

” ‘Between one-quarter and one-third of patients got long-term clinical benefit,’ said Geoffrey Shapiro, MD, PhD, director of Dana-Farber’s Early Drug Development Center. ‘Several patients were on the drugs for more than a year, and one patient has been on treatment for two and a half years. And these were heavily-treated patients without many options.’ ”

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Requirement for Interaction of PI3-Kinase p110α with RAS in Lung Tumor Maintenance

“RAS proteins directly activate PI3-kinases. Mice bearing a germline mutation in the RAS binding domain of the p110α subunit of PI3-kinse are resistant to the development of RAS-driven tumors. However, it is unknown whether interaction of RAS with PI3-kinase is required in established tumors. The need for RAS interaction with p110α in the maintenance of mutant Kras-driven lung tumors was explored using an inducible mouse model.”


Phosphoproteomic Characterization of DNA Damage Response in Melanoma Cells Following MEK/PI3K Dual Inhibition

“Growing evidence suggests that successful intervention in many human cancers will require combinations of therapeutic agents. Critical to this effort will be a detailed understanding of the crosstalk between signaling networks that modulate proliferation, cell death, drug sensitivity, and acquired resistance. Here we investigated DNA-damage signaling elicited by small-molecule inhibitors against MAP/ERK kinase (MEK) and PI3K in melanoma cells. This work, performed using cutting-edge mass spectrometry proteomics, uncovered a burst of signaling among proteins in the DNA-damage pathway upon initiation of the cell-death program by agents targeting the RAS–RAF–MEK and PI3K–AKT–mTOR pathways. These signals may prove important to the short- and long-term sensitivity of tumor cells to MEK- and PI3K-targeted therapies.”


mTORC1 Status Dictates Tumor Response to Targeted Therapeutics

“Genomics has revolutionized and personalized our approach to cancer therapy, with clinical trials now frequently involving patient stratification based on tumor genotype. Rational drug design specifically targeting the most common genetic events and aberrantly regulated pathways in human cancers makes this approach possible. However, our understanding of the wiring of oncogenic signaling networks and the key downstream effectors driving human cancers is incomplete, limiting our ability to predict clinical responses or identify mechanisms of resistance to targeted therapeutics. Recent studies in independent cancer lineages driven by distinct oncogenic signaling events point to a common downstream target, the mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1), which dictates the cellular and clinical response to pathway-specific inhibitors. mTORC1 is a highly integrated signaling node that promotes anabolic cell growth and proliferation and lies downstream of multiple oncogenes and tumor suppressors, including those influencing the PI3K-Akt and RAS-RAF-MEK-ERK pathways. Studies are now suggesting that to effectively target the major oncogenic signaling pathway in a given tumor, mTORC1 must be inhibited, and that its sustained activation is a major mechanism of resistance to such targeted therapies.”


ETV4 Promotes Metastasis in Response to Activation of PI3-Kinase and Ras Signaling in a Mouse Model of Advanced Prostate Cancer

“Combinatorial activation of PI3-kinase and RAS signaling occurs frequently in advanced prostate cancer and is associated with adverse patient outcome. We now report that the oncogenic Ets variant 4 (Etv4) promotes prostate cancer metastasis in response to coactivation of PI3-kinase and Ras signaling pathways in a genetically engineered mouse model of highly penetrant, metastatic prostate cancer. Using an inducible Cre driver to simultaneously inactivate Pten while activating oncogenic Kras and a fluorescent reporter allele in the prostate epithelium, we performed lineage tracing in vivo to define the temporal and spatial occurrence of prostate tumors, disseminated tumor cells, and metastases. These analyses revealed that though disseminated tumors cells arise early following the initial occurrence of prostate tumors, there is a significant temporal lag in metastasis, which is temporally coincident with the up-regulation of Etv4 expression in primary tumors. Functional studies showed that knockdown of Etv4 in a metastatic cell line derived from the mouse model abrogates the metastatic phenotype but does not affect tumor growth. Notably, expression and activation of ETV4, but not other oncogenic ETS genes, is correlated with activation of both PI3-kinase and Ras signaling in human prostate tumors and metastases. Our findings indicate that ETV4 promotes metastasis in prostate tumors that have activation of PI3-kinase and Ras signaling, and therefore, ETV4 represents a potential target of therapeutic intervention for metastatic prostate cancer.”


National Cancer Institute's 'RAS Project' Takes Aim at Common Cancer-Driving Protein

The National Cancer Institute (NCI) is organizing a massive collaborative initiative between its laboratory and hundreds of outside researchers to discover cancer treatments targeting a class of genes called RAS genes and their products, RAS proteins. RAS genes, including their most common form, KRAS, are mutated in one-third of all cancers. Although the important role of RAS in cancer has been known for over 30 years, no treatments targeting RAS have been developed so far, because RAS proteins lack a ‘binding site’ where drugs could attack. However, recent research has uncovered potential weaknesses in RAS that future treatment might exploit. The NCI’s RAS Project aims to ‘crowdsource’ the expertise of many researchers to better understand and tackle RAS.


National Cancer Institute's 'RAS Project' Takes Aim at Common Cancer-Driving Protein

The National Cancer Institute (NCI) is organizing a massive collaborative initiative between its laboratory and hundreds of outside researchers to discover cancer treatments targeting a class of genes called RAS genes and their products, RAS proteins. RAS genes, including their most common form, KRAS, are mutated in one-third of all cancers. Although the important role of RAS in cancer has been known for over 30 years, no treatments targeting RAS have been developed so far, because RAS proteins lack a ‘binding site’ where drugs could attack. However, recent research has uncovered potential weaknesses in RAS that future treatment might exploit. The NCI’s RAS Project aims to ‘crowdsource’ the expertise of many researchers to better understand and tackle RAS.


National Cancer Institute's 'RAS Project' Takes Aim at Common Cancer-Driving Protein

The National Cancer Institute (NCI) is organizing a massive collaborative initiative between its laboratory and hundreds of outside researchers to discover cancer treatments targeting a class of genes called RAS genes and their products, RAS proteins. RAS genes, including their most common form, KRAS, are mutated in one-third of all cancers. Although the important role of RAS in cancer has been known for over 30 years, no treatments targeting RAS have been developed so far, because RAS proteins lack a ‘binding site’ where drugs could attack. However, recent research has uncovered potential weaknesses in RAS that future treatment might exploit. The NCI’s RAS Project aims to ‘crowdsource’ the expertise of many researchers to better understand and tackle RAS.


U.S. Cancer Institute 'Megaproject' to Target Common Cancer-Driving Protein

“It may be dealing with the worst budget crunch in its history, but that is not stopping the National Cancer Institute (NCI) from doing new things. Today, NCI officials outlined a plan to bring together the agency’s contract lab in Frederick, Maryland, and outside researchers to find ways to block a mutated protein that drives growth in one-third of all cancers but was thought impossible to “drug” until now.”