Finding ways to fight cancer

Scripps receives philanthropic support from Frenchman’s Creek Women for Cancer Research

Here’s a sobering thought.  For men, chances of developing prostate cancer are one out of two. For women, chances of developing cancer are one in three, with breast cancer being the biggest culprit.

In 2009, in the United States, 175,000 women got breast cancer, and 45,000 died of the disease. 190,000 men got prostate cancer, and 40,000 died of the disease.

But there are survivors: 2.5 million women have survived breast cancer; 2 million men have survived prostate cancer. Those successes came about because of medical advancements in the last 30 years, when the survival rate was 70 percent for women and 67 percent for men. Those rates are now 88 percent for women and 90 percent for men.

Cancer research, like that done at Scripps, helps. And it needs funding.  Most money that funds research comes from the National Institute of Health, but the funding rates dropped two-thirds since 2000.  To help take up the slack, Frenchman’s Creek Women for Cancer Research has raised more than $400,000 to support three cancer research  fellows in cancer biology at Scripps.

Working with Howard Petrie and Kendall Nettles, the fellows have made inroads in advancing research in the role of the immune system in cancer and the impact of steroid hormones, and how notch3, a key regulatory protein and known cause of cancer, contributes to the development or progression of cancer.

In January, Scripps professors gave a presentation to those donors, updating them on their research activities and 2010 achievements.

To give an overview on research to help those 30 percent of patients with estrogen-receptor positive breast cancer who are resistant to the drug, Tamoxifen, Howard Petrie, Ph.D., professor in the division of immunology at Scripps’ Department of Cancer Biology, spoke about the roll in biology and cancer of the notch3 gene and the proteins that are encoded by them.

The notch protein sits like a trigger and penetrates the cell membrane, he said. “On the outside, notch has a bunch of repeats (of amino acids). On the inside there’s also a lineup of some repeats with different functions. Both the inside part and the outside part of notch interact with specific types of proteins.”

When the outside part is connected to a specific protein, the inside part is cleaved and released within the cell, then enters the cell nucleus and binds with DNA.

“Notch is a master mediator of how genes encode proteins,” he said. “When this process, though, goes awry, it leads to cancer.”

All multi-cellular animals have one or more notch genes. Humans have four. Notch1 protein has clearly defined roles in biology and cancer in a wide variety of tissues, including the mammary and prostate.

But, not much is known about notch3, he said. “What we do know is that it’s implicated in cancer.  Despite its importance in biology and the obvious links to cancer, we don’t know that much about it, nor do we know how to correct its function when it goes awry.

Scripps researchers have developed a genetic resource for understanding the function of notch3, showing its structure. “What we did was replace the intracellular piece with a bacterial enzyme not found in mammals, and that allows us to encode notch3 that has that enzyme and specifically identify it in the animal.

“We don’t understand that much about notch3, but we have screened the chemical libraries and identified 51 drugs that activate the notch pathway (the process where both parts of notch are activated).

“These are small chemical compounds, when put on the stem cell, activate the notch3 pathway. In other words, we can see which cells attach to which cell in the notch3 protein.”

In 2010. Scripps professors wrote a manuscript citing women’s cancer research.  “Our research has shown that two proteins encoded by the Notch family of genes, both of which are implicated in cancer, have distinct and non-overlapping functions, and thus are unlikely to be targeted by the same drug regimens,” he said.

In clinical endocrine therapy (therapies that deal with hormones), Tamoxifen treatment blocks the estrogen signals and that’s the most effective treatment for patients with ER (estrogen receptor) positive breast cancer. However, some of those tumors are resistant to treatment and metastasize.

Possible strategies to solve this: To find biomarkers (a biomarker is anything that can be used as an indicator of a particular disease state) that can predict which cancer will be Tamoxifen-resistant so that doctors can use other strategies to treat those kinds of cancers. And to find drugs that can kill cancers that Tamoxifen missed.

Kendall Nettles, Ph.D. an associate professor in he Department of Cancer Biology, is working to make new types of estrogen therapy. Current therapies block growth of estrogen, he said, which is good because estrogen promotes growth of breast cancer, but estrogen is also anti-inflammatory. Ju-Li Luo, (Ph.D., assistant professor in the Department of Cancer Biology) discovered that inflammation can be associated with cancer production, Nettles added.

Tamoxifen works by wrapping around the estrogen receptor, replacing the estrogen, and changing the shape of the receptor and its activity. Then the receptor can interact with different proteins with an end result of turning off the growth of cancer.

“The drug Tamoxifen blocks both estrogen and its anti-inflammatory properties, and we’d like to find drugs that will block tumor growth and inflammation and that will be a new way to prevent treatment-resistant cancer,” he said.

Last fall, Scripps scientists published a study in Nature Chemical Biology on their findings that in working with the molecular systems that recognize the hormone estrogen, that as protein receptors change shape, ligands can adapt to that change, binding productively to both active and inactive structures.

Nettles is excited by the possibility of working with an ensemble of ligand arrangements, combining one with anti-inflammatory properties (which plays a role in cancer) and with another that blocks tumor growth – potentially doubling the effectiveness of the treatment.  Nettles said, “If ligand dynamics turn out to be a general feature of small molecule signaling, our findings could transform our approach to finding improved cancer therapies.”

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