New System Finds and Targets Vulnerabilities in Lung Cancer Cells

Excerpt:

“Genetic changes that help lung cancer thrive also make it vulnerable to a promising experimental drug, according to a study led by researchers from Perlmutter Cancer at NYU Langone Health, and published online October 2 in Nature Medicine.

“Specifically, the study found that mutations in the DNA code for the gene KEAP1 help lung adenocarcinoma  counter a process called oxidative stress, in which molecules known as reactive oxygen species (ROS) are created as a side effect of ‘burning’ fuel to make energy. Cancer cells need extra fuel to support abnormal growth, produce more ROS, and depend more for survival on naturally occurring antioxidants that keep ROS from damaging cell parts.”

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The Trouble With KRAS


Mutations in the gene that encodes the KRAS protein are frequently encountered in various human cancers. They are found in about 30% of non-small cell lung cancers (NSCLCs), making KRAS the single most common gene mutated in this cancer. The rate of KRAS mutations in other cancers, such as pancreatic or colorectal, is even higher.

A mutant KRAS protein that is always in the “on” position activates many signaling pathways, many of which lead to unrestrained growth and proliferation of cancer cells. This makes KRAS an appealing treatment target. However, challenges abound, and researchers are exploring several different approaches to treating KRAS-mutant cancers.

Unlike mutations in proteins known as receptor tyrosine kinases, like EGFR or ALK, mutated KRAS is a very difficult protein to target with cancer drugs. (So much so that the National Institutes of Health (NIH) has undertaken a special effort to intensify the effort towards successful targeting of mutant KRAS, known as the RAS Initiative.) Continue reading…


MEK Inhibitor Disappoints in KRAS-Mutant NSCLC

Excerpt:

“A targeted combination therapy for patients with KRAS-mutant non-small cell lung cancer (NSCLC) did not improve overall survival (OS) or progression-free survival (PFS), researchers reported.

“The phase III, randomized SELECT-1 trial compared the experimental MEK inhibitor selumetinib, in combination with docetaxel (Taxotere), with docetaxel and placebo as second-line therapy in patients who failed a previous line of therapy, explained Pasi Jänne, MD, PhD, of the Dana Farber Cancer Institute in Boston, and colleagues.

“After a follow-up of approximately 1 year, median OS in the selumetinib combination group was 8.7 months versus 7.9 months in the docetaxel plus placebo group (hazard ratio 1.05, 95% CI 0.85-1.30, P=0.64), they wrote in JAMA.

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Scientists Find Lethal Vulnerability in Treatment-Resistant Lung Cancer

Excerpt:

“Researchers working in four labs at UT Southwestern Medical Center have found a chink in a so-called ‘undruggable’ lung cancer’s armor — and located an existing drug that might provide a treatment.

“The study, published this week in Nature, describes how the drug Selinexor (KPT-330) killed lung cancer cells and shrank tumors in mice when used against cancers driven by the aggressive and difficult-to-treat KRAS cancer gene. Selinexor is already in clinical trials for treatment of other types of cancer, primarily leukemia and lymphoma but also gynecological, brain, prostate, and head and neck cancers.”

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Scientists Find Lethal Vulnerability in Treatment-Resistant Lung Cancer

Excerpt:

“Researchers working in four labs at UT Southwestern Medical Center have found a chink in a so-called ‘undruggable’ lung cancer’s armor – and located an existing drug that might provide a treatment.

“The study, published this week in Nature, describes how the drug Selinexor (KPT-330) killed cells and shrank tumors in mice when used against cancers driven by the aggressive and difficult-to-treat KRAS cancer gene. Selinexor is already in clinical trials for treatment of other types of cancer, primarily leukemia and lymphoma but also gynecological, brain, prostate, and head and neck cancers.”

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AstraZeneca Provides Update on Phase III Trial of Selumetinib in Non-Small Cell Lung Cancer

Excerpt:

“AstraZeneca today announced results from the Phase III SELECT-1 trial of the MEK 1/2 inhibitor, selumetinib, in combination with docetaxel chemotherapy as 2nd-line treatment in patients with KRAS mutation-positive (KRASm) locally-advanced or metastatic non-small cell lung cancer (NSCLC).

“The results showed that the trial did not meet its primary endpoint of progression-free survival (PFS), and selumetinib did not have a significant effect on overall survival (OS). The adverse event profiles for selumetinib and docetaxel were consistent with those seen previously.”

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Targeted Therapies Beneficial in KRAS-Mutated NSCLC

Excerpt:

“Targeted therapies that do not contain erlotinib can be beneficial for patients with KRAS-mutated (KRAS mut+) advanced non-small-cell lung cancer (NSCLC), according to a study published online Aug. 1 in the Journal of Clinical Oncology.

“Vassiliki Papadimitrakopoulou, M.D., from the University of Texas MD Anderson Cancer Center in Houston, and colleagues examined the effects of targeted therapies in NSCLC. Patients were randomized to four arms: erlotinib (22 patients), erlotinib plus MK-2206 (42 patients), MK-2206 plus AZD6244 (75 patients), or sorafenib (61 patients).

“The researchers found that the primary end point of an eight-week disease control rate (DCR) was 48 percent in all 186 evaluable patients (32, 50, 53, and 46 percent, respectively, for the four treatment arms). For the 27 percent of patients who were KRAS mut+, DCR was 20, 25, 62, and 44 percent, respectively, compared with 36, 57, 49, and 47 percent, respectively, for KRAS wild-type patients. Median progression-free survival was 2.0 months: 1.8 and 2.5 months for arms 1/2 and 3/4, respectively, in KRAS mut+ patients (P = 0.04). In KRAS wild-type patients, median overall survival was 6.5 months: 9.0 and 5.1 months in arms 1/2 and 3/4, respectively (P = 0.03).”

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New RAF-targeted Therapeutic Shows Early Promise Against Tumors With BRAF and RAS Mutations

Excerpt:

“The new investigational anticancer therapeutic BGB-283, which targets the RAF family of proteins, was safe, tolerable, and showed signs of clinical activity in patients who had a range of types of cancer with mutations in BRAF, KRAS, and NRAS, according to results from a phase I clinical trial presented here at the AACR Annual Meeting 2016, April 16-20.

“ ‘BRAF gene mutations fuel cancer cell proliferation and survival in a number of types of cancer, including melanoma, and thyroid and colorectal cancers,’ said Jayesh Desai, FRACP, a medical oncologist at The Royal Melbourne Hospital in Melbourne, Australia. ‘In melanoma, the BRAF V600E mutation predominates, and specific inhibitors of the BRAF V600E mutant protein have been approved for treating patients with melanoma with BRAF V600E gene mutations.’ ”

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Possible Treatment on Horizon for Advanced KRAS-Mutant NSCLC

Excerpt:

“Promising early phase clinical trials have led to the initiation of the phase III JUNIPER trial, which is assessing abemaciclib (LY2835219) for patients with previously treated KRAS-mutant lung cancer, a traditionally hard to treat genetic subtype.

“JUNIPER is an open label phase III study currently recruiting patients with stage IV non–small cell lung cancer (NSCLC) with a detectable KRAS mutation who have progressed following treatment with platinum-based chemotherapy (NCT02152631). Patients will be randomized to receive either abemaciclib or erlotinib, both with best supportive care.

“ ‘KRAS mutations are common in patients with NSCLC, but there have been few clinical advances in our treatment for these patients,’ said investigator Jonathan W. Goldman, MD, of the Department of Medicine, Hematology/Oncology, member of the Signal Transduction and Therapeutics Program Area at UCLA’s Jonsson Comprehensive Cancer Center, who explored the drug in a phase I trial.”

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