Nav: Home

Mechanism of an effective MEK inhibitor identified

November 01, 2016

PHILADELPHIA -- (Nov. 1, 2016) -- Understanding the effects of certain targeted therapies on antitumor immunity is necessary to design combined interventions for more effective cancer treatment. In the past, data have shown that trametinib, an FDA-approved MEK inhibitor routinely administered to patients with melanoma and currently being studied to treat a number of other types of cancer, inhibits T cell responses in vitro, but is effective in some tumor models in vivo.

Scientists at The Wistar Institute recently discovered how this drug boosts antitumor activity and slows tumor progression, even if it fails to directly stop tumor cell proliferation. Study results were published in the journal Cancer Research.

When small molecule kinase inhibitors -- a class of drugs designed to target specific mutations and proteins related to cancer while sparing healthy cells without these mutations -- started being approved for different types of cancer, the laboratory of José R. Conejo-Garcia, M.D., Ph.D., professor in the Tumor Microenvironment and Metastasis Program at Wistar, initiated a project to understand the effects of these targeted therapies on immune response.

"We realized that most small kinase inhibitors in the pipeline targeted pathways that are important for the function of immune cells," Conejo-Garcia said. "However, they had been primarily tested in vitro against tumor cells or in immunodeficient animals at best. Very little was known about the consequences of using these interventions on spontaneous or immunotherapeutically boosted antitumor immunity."

In this study, Conejo-Garcia and colleagues found that trametinib controls tumor progression by halting the mobilization of myeloid-derived suppressor cells (MDSCs), a set of immune cells that have been linked to making tumors resistant to treatment. This reduced the level of immune suppression in the tumor, allowing anti-tumor T cells to target the tumor. In fact, the effectiveness of trametinib is dependent on the activity of these anti-tumor T cells, despite its direct inhibitory effects on this tumor cell compartment, which are largely rescued by certain cytokines present at tumor beds.

Although trametinib failed to directly inhibit tumor cell proliferation, its combined effects on multiple immune and nonimmune compartments boosted antitumor immunity in vivo in tumor-bearing hosts and significantly delayed malignant progression.

"Understanding the effects of trametinib on antitumor immunity is urgently needed to design the sequence of rational combinatorial interventions that include emerging and future anticancer immunotherapies," Conejo-Garcia said. "Our findings demonstrate that trametinib could be combined with existing immunotherapeutic agents in at least tumors that mobilize a significant amount of immunosuppressive myeloid cells."
-end-
This work was supported by the National Institutes of Health/National Cancer Institute grants R01CA157664, R01CA124515, R01CA178687, T32CA009171, and T32CA009140, The Jayne Koskinas & Ted Giovanis Breast Cancer Research Consortium at Wistar, and Ovarian Cancer Research Fund Alliance (OCRFA) Program Project Development awards. Co-author Alfredo Perales-Puchalt was supported by the Ann Schreiber Award (OCRFA). Support for shared resources used in this study was provided by Cancer Center Support Grant (CCSG) CA010815 to The Wistar Institute.

Co-authors of this study from The Wistar Institute include Michael J. Allegrezza, Melanie R. Rutkowski, Tom L. Stephen, Nikolaos Svoronos, Alfredo Perales-Puchalt, Jenny M. Nguyen and Kyle K. Payne. Sunil Singhal, Evgeniy B. Eruslanov and Julia Tchou from the University of Pennsylvania were also co-authors of this study.

The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

The Wistar Institute

Related Cancer Articles:

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.
Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.
Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.
Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: The Power Of Spaces
How do spaces shape the human experience? In what ways do our rooms, homes, and buildings give us meaning and purpose? This hour, TED speakers explore the power of the spaces we make and inhabit. Guests include architect Michael Murphy, musician David Byrne, artist Es Devlin, and architect Siamak Hariri.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at Radiolab.org/donate.     You can read The Transition Integrity Project's report here.