Hard-to-treat Myc-driven cancers may be susceptible to drug already used in clinic

December 14, 2012

PHILADELPHIA -- Drugs that are used in the clinic to treat some forms of breast and kidney cancer and that work by inhibiting the signaling molecule mTORC1 might have utility in treating some of the more than 15 percent of human cancers driven by alterations in the Myc gene, according to data from a preclinical study published in Cancer Discovery, a journal of the American Association for Cancer Research.

"More than 1 million people diagnosed with cancer each year have a tumor driven by alterations in the Myc gene," said Grant A. McArthur, M.D., Ph.D., professor of translational research at the Peter MacCallum Cancer Centre in Melbourne, Australia. "However, it has proven impossible to develop drugs that effectively target Myc.

"One of Myc's functions is to regulate cell growth. Because mTORC1 is also a regulator of cell growth, we hypothesized that inhibiting mTORC1 with the drug everolimus might suppress Myc-driven tumor initiation and growth."

McArthur and his colleagues tested their hypothesis in a mouse model of Myc-driven lymphoma and found that treatment with everolimus provided strong protection against disease: only four of 33 mice treated with everolimus developed lymphoma, while 22 of 34 mice treated with placebo developed the disease.

In addition, treatment with everolimus led to tumor regression and significantly improved survival compared with placebo in mice with established lymphomas. However, all of these mice eventually relapsed as a result of the growth of lymphoma cells resistant to the effects of everolimus.

"These data confirmed our hypothesis that mTORC1 inhibition could suppress Myc-driven tumor initiation and growth," said McArthur. "The surprise was found in how mTORC1 inhibition led to tumor regression. We had expected that it would trigger cancer cells to die by a cellular process known as apoptosis, but we found that this was not the case."

Detailed analysis of the tumors indicated that everolimus caused tumor regression by inducing cellular senescence.

According to McArthur, normal cells protect themselves when cancer-driving genes are switched on is by entering a state called senescence. When cancers develop, they have found ways to overcome this safeguard. "Our data indicate that one way in which cancers bypass senescence, in particular senescence induced by Myc, is through a signaling pathway involving mTORC1," he said.

Resistance to everolimus treatment in mice with established lymphomas was associated with loss of the function of p53, a protein known to help suppress tumor formation and growth.

"The loss of effectiveness of everolimus therapy against lymphoma cells deficient in p53 function has important clinical implications," said McArthur. "Everolimus could be a useful new string to the bow for clinicians treating patients with Myc-driven cancers, in particular B cell lymphomas, but that it would be helpful only to those patients with functional p53."
-end-
Follow the AACR on Twitter: @aacr #aacr
Follow the AACR on Facebook: http://www.facebook.com/aacr.org

About the American Association for Cancer Research

Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 17,000 attendees. In addition, the AACR publishes seven peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer.

For more information about the AACR, visit www.AACR.org.

American Association for Cancer Research

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

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.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.