Research: Epigenetic factor reduces sensitivity of breast cancer cells to common cancer drug

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In continuation of my update on lapatinib

A surprising, paradoxical relationship between a tumor suppressor molecule and an oncogene may be the key to explaining and working around how breast cancer tumor cells become desensitized to a common cancer drug, found researchers at the Perelman School of Medicine at the University of Pennsylvania. The drug, lapatinib, activates the suppressor called FOXO, in HER2+ breast cancer cells, but then FOXO becomes a turncoat molecule, working with an epigenetic regulator that controls gene expression. This drug-triggered relationship induces the expression of the oncogene c-Myc, leading to reduced sensitivity to the cancer drug and eventually relapse. They published their cover article today in Cancer Cell.

"We found that an epigenetic pathway is crucial for growth of HER2+ cells and this epigenetic factor reduces sensitivity of the cancer cells to lapatinib, a HER2 inhibitor," said senior author Xianxin Hua, MD, PhD, a professor of Cancer Biology. "We need to understand how the body initially responds to these drugs and why there is a relapse and devise a new tool to fix that."

Human epidermal growth factor receptor 2 (HER2) is upregulated in a subset of human breast cancers. The HER2 pathway is mutated in many cancers, which drives tumors, but inhibitors of this pathway, such as lapatinib, have only limited success because cancer cells quickly adapt.

FOXO was normally thought of as the "good guy" molecule that controls cancerous cell growth, while c-Myc, the cancer-promoting molecule, the "bad guy." However, FOXO becomes the agent that desensitizes cells to cancer drugs, so this "good guy" molecule is converted to a "bad guy," during the treatment of the cancer cells with the anti-cancer drug.

"Now that we know about this triangle among FOXO, c-Myc, and the epigenetic pathway, we can stop c-Myc with an epigenetic inhibitor," Hua said. "Multiple epigenetic regulators participate in the drug-desensitizing pathway, so they could serve as new targets to improve therapy for this type of cancer."

Research: Epigenetic factor reduces sensitivity of breast cancer cells to common cancer drug

New anti-cancer drug may protect normal cells against radiation

Although radiation treatments have become much more refined in recent years, it remains a challenge to both sufficiently dose the tumor while sparing the surrounding tissue. A new anti-cancer drug, already in clinical development, may help address this issue by protecting normal cells - but not the cancer - from the effects of radiation. The research, published November 14th in Molecular Cancer Therapeutics, further suggests this drug may also be useful in treating accidental exposure to radiation.

"It was a stroke of luck that the drug that most effectively protected normal cells and tissues against radiation also has anti-cancer properties, thus potentially increasing the therapeutic index of radiation therapy," says Ulrich Rodeck, M.D., Ph.D., Professor of Dermatology and Cutaneous Biology and Radiation Oncology at Thomas Jefferson University, and senior author on the study.

Together with first author Vitali Alexeev, Ph.D., Assistant Professor, Dermatology and Cutaneous Biology, Dr. Rodeck and colleagues tested five compounds that were shown to have radiation-protective properties in earlier studies. The researchers gave the mice one of the five compounds a day before and for several days after radiation treatment. A compound called RTA 408 emerged from this screen as a robust radiation protector and its effect was comparable to the only drug currently approved by the FDA for that purpose. (The approved drug, called amifostine, however, has a number side effects including severe nausea or vomiting that make it an unappealing choice for clinicians.) Sites that are usually most susceptible to radiation damage including the gut and blood cells in the bone marrow were both protected in mice treated with RTA 408.

Ref : http://mct.aacrjournals.org/content/early/2014/11/12/1535-7163.MCT-14-0354.abstract?sid=22fc8faf-65af-4c60-8a08-265701e2f6ad

New anti-cancer drug may protect normal cells against radiation

Unexpected use of former cancer drug, Zebularine...

Researchers at Lund University have unexpectedly discovered that an old cancer drug can be used to prevent rejection of transplanted tissue. The researchers now have high hopes that their discovery could lead to new treatments for both transplant patients and patients with autoimmune diseases.

"Our group were studying the effects of the old tumour drug Zebularine, (see structure) developed in the USA in the 1960s, and by chance we discovered that it had completely unexpected effects on the immune system," says Leif Salford, Senior Professor of Neurosurgery.

"It turned out that Zebularine has the ability to subdue the reaction of the body's immune system. This could be important in situations where tissue or organs are transplanted. We also think it could be used to curb the body's attacks on its own tissue in autoimmune diseases, for instance type 1 diabetes or rheumatoid arthritis," says Dr Nittby.

In studies on animals, the researchers used rats that were made diabetic. The researchers transplanted the islets of Langerhans  cell groups in the pancreas producing insulin -- from healthy rats from another kind of rat into those with diabetes. The diabetic rats were divided into two groups; one group were treated with Zebularine and the other, the control group, did not receive any treatment. The diabetic rats that were treated with Zebularine survived for a significantly longer period than the untreated rats.

"It is very interesting that we only treated them with Zebularine for two weeks, but the effects of the treatment could be observed throughout the 90-day follow-up period.

"The findings are very exciting and are a sign that the immune system was not just generally suppressed, but that the treatment was more targeted. Neither did we see any signs of side-effects," said Dr Nittby.

The researchers are now working intensively to further refine the treatment. The next step is to teach certain cells in the immune system -- the dendritic cells -- to accept certain specific proteins using the Zebularine treatment. This would mean that the treatment could be targeted even more.

Unexpected use of former cancer drug