Nav: Home

Combination therapy targets genetic mutation found in many cancers

June 02, 2017

HOUSTON - A study at The University of Texas MD Anderson Cancer Center has shown promise for effective treatment of therapy-resistant cancers caused by a mutation of the RAS gene found in many cancers. The pre-clinical study combined therapies targeting the inhibitors polyADP ribose polymerase (PARP) and mitogen-activated protein kinase (MEK). The findings were published this week in Science Translational Medicine.

Mutations in the RAS gene account for more than 90 percent of pancreatic cancers, 50 percent of colorectal cancers, and 30 percent of lung cancers, and a significant portion of many other types of tumors. Unfortunately, these cancers are usually resistant to traditional treatments contributing to poor patient outcomes.

"Nowhere is the need for targeted therapies greater than for cancers driven by oncogenic RAS, which represents the most common type of potentially targetable mutation in cancer," said Gordon Mills, M.D., Ph.D., chair of Systems Biology. "Our study demonstrated that the rational combination of PARP and MEK inhibitors warrants clinical investigation in patients with RAS-mutant tumors where there are few effective therapeutic options."

PARP inhibitors block a key pathway for cellular DNA repair, effectively stopping many cancers with defects in DNA repair from growing, but the disease soon gains resistance due to the tumor's cell ability to adapt to stresses caused by the therapy. MEK inhibitors also are used to affect pathways often overactive in some cancers.

Mills' team found that combinations of PARP and MEK inhibitors evoked "unexpected cytotoxic effects" in vitro and in vivo in multiple RAS-mutant tumor models across tumor lineages where RAS mutations are prevalent. The combination therapy worked independent of mutations in tumor suppressor genes including BRCA1, BRCA2 and p53, suggesting the dual therapy's potential as a treatment for multiple RAS-mutant cancers. It also was effective for tumors that had become resistant to PARP, as well as in cells that did not have aberrations in BRCA1 and BRCA2, suggesting the combination could expand to a wide spectrum of patients likely to benefit.

"The sensitivity of RAS-mutant cells to the combination appears to be independent of intrinsic gene expression patterns, as observed across multiple different lineages," said Mills. "Because the synergistic responses to MEK1 and PARP1 combinations also were independent of p53 mutation status, the approach should be effective in both normal and mutant p53 tumors. Together, the in vitro and in vivo data argue that a MEK1 and PARP1combination offer the potential to induce cell death and increase the magnitude, duration and spectrum of PARP activity."

Currently, clinical trials in this area of investigation are under consideration at MD Anderson.
MD Anderson research team members included Chaoyang Sun, Ph.D., Yong Fang, Ph.D., Jun Yin, Ph.D., Jian Chen, Ph.D., Dong Zhang, Ph.D., Xiaohua Chen, Ph.D., Christopher Vellano, Ph.D., Kang Jing Jeong, Ph.D., Yiling Lu, M.D., and Shiaw-Yih Lih, Ph.D., all of Systems Biology; Zhenlin Ju, Ph.D., Bioinformatics and Computational Biology; Patrick Kwok-Shing Ng, Ph.D., Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy; Shannon Westin, M.D., Gynecologic Oncology and Reproductive Medicine; and Guang Peng, M.D., Ph.D., Clinical Cancer Prevention.

Other participating institutions included Tongji Medical College, Wuhan, China; Zhejiang University School of Medicine, Hangzhou, China; University of California, San Francisco; Baylor College of Medicine, Houston; and Harvard Medical School, Boston.

The study was funded by the National Institutes of Health (SU01CA168394, SP50CA098258, SP50CA083639, and CA016672); Susan G. Komen (SAC110052); the Andrew Sabin Family Fellowship program; and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

University of Texas M. D. Anderson Cancer Center

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Related Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Climate Crisis
There's no greater threat to humanity than climate change. What can we do to stop the worst consequences? This hour, TED speakers explore how we can save our planet and whether we can do it in time. Guests include climate activist Greta Thunberg, chemical engineer Jennifer Wilcox, research scientist Sean Davis, food innovator Bruce Friedrich, and psychologist Per Espen Stoknes.
Now Playing: Science for the People

#527 Honey I CRISPR'd the Kids
This week we're coming to you from Awesome Con in Washington, D.C. There, host Bethany Brookshire led a panel of three amazing guests to talk about the promise and perils of CRISPR, and what happens now that CRISPR babies have (maybe?) been born. Featuring science writer Tina Saey, molecular biologist Anne Simon, and bioethicist Alan Regenberg. A Nobel Prize winner argues banning CRISPR babies won’t work Geneticists push for a 5-year global ban on gene-edited babies A CRISPR spin-off causes unintended typos in DNA News of the first gene-edited babies ignited a firestorm The researcher who created CRISPR twins defends...