What Lies Beneath

In the world of cancer, it is no longer enough to prescribe chemotherapies that blast tumor cells while taking out healthy cells and causing major side effects in the process. Physicians want to do more. And to do more, they must know more. Researchers are doggedly trying to understand exactly how cancer cells work on a genetic and molecular level — and then using that information against them.

Count the members of City of Hope’s Gastrointestinal Oncology Program among the search party. Whether they are surgeons looking for an advantage against colon cancer or physicians trying to demystify pancreatic tumors, these healers are headed to the laboratory.

By studying the proteins and enzymes that make cancer tick, they are on their way to designing more effective and less damaging treatments.

Short-circuiting pancreatic cancer

Pancreatic cancer continues to defy modern medicine. The location of the pancreas deep in the abdomen allows the disease to hide and advance long before symptoms reveal themselves, so pancreatic cancer remains difficult to treat successfully.

Two City of Hope researchers — Joseph Kim, M.D., and Nagarajan Vaidehi, Ph.D. — have teamed up to short-circuit this aggressive cancer. They aim to catch the cancer early by looking for signs of changes that lead to the cancer, explained Kim, associate professor of surgery.

While Kim is a surgeon fascinated by the riddles of basic science, Vaidehi is a biologist who brings her expertise in using computer modeling for drug design together with a desire to improve clinical care. They make a keen scientific match.

Their work began through Kim’s investigations into the receptor CXCR4, which is involved in the spread of pancreatic cancer. Receptors are special proteins in cells; when other molecules attach to these receptors, they can trigger or block an action, much like a key turning in a keyhole unlocks or locks a door. He found that abnormal pancreatic cells express high levels of CXCR4 when they begin to turn cancerous.

Vaidehi screened about 300,000 chemical compounds to identify those that might bind with CXCR4 and inhibit it, potentially blocking cancer growth. She found two — and both compounds already have proven safe in phase I clinical trials for other conditions. This will enable Kim and Vaidehi to eliminate several years in the clinical trials process and move the drugs straight to phase II clinical trials against pancreatic cancer.

In pancreatic cancer, several proteins appear to have influence. The researchers are now testing compounds against the receptor CCR9, which causes pancreatic cancer cells to grow and become more aggressive, according to Kim’s lab studies.

Vaidehi is working with John Shively, Ph.D., chair of the Department of Immunology, to develop a sensitive imaging agent to detect high levels of CXCR4 using positron emission tomography, commonly known as a PET scan. That may help detect pancreatic lesions when they are more readily treatable.

Ultimately, Vaidehi said, “we hope to make progress so we can help people who have one of the deadliest cancers.”

Avoiding rectal cancer surgery

Julio Garcia-Aguilar, M.D., Ph.D., chairs City of Hope’s Department of Surgery, but he focuses much of his research on trying to help rectal cancer patients avoid going under the scalpel.

Surgery can significantly affect quality of life for patients with rectal cancer because many will need a permanent colostomy, a new outlet for the colon’s waste, said Garcia-Aguilar. In search of a better alternative to surgery, Garcia-Aguilar is leading a multi-institution National Institutes of Health study to find whether chemoradiation — chemotherapy plus radiation — may kill rectal cancer so well that some patients can avoid surgery altogether. The results, so far, are encouraging.

Typically, patients with rectal cancer first undergo a round of chemoradiation, then have surgery six weeks later and finish with a second round of chemoradiation. In the group’s initial study, investigators lengthened the span between the first chemoradiation and surgery to 16 weeks. When they performed the surgeries, they found no residual, viable tumor cells in the tissue of more than 30 percent of the patients studied.

Assuming this number held true in a larger population, “almost 10,000 people could potentially avoid surgery,” said Garcia-Aguilar.

He and his colleagues now are studying whether genetic biomarkers can forecast which patients will benefit from chemoradiation. Biomarkers are biological clues, like genetic mutations, that are unique to certain patients’ cancers. So far, they have discovered who will not respond: patients who have gene mutations in both the p53 and Kras proteins, which are found in a variety of cancers.

“It may be easier to identify resistance [to therapy] than responsiveness,” noted Garcia-Aguilar.

The group’s next study will focus on patients with stage 2 and 3 rectal cancer who receive chemoradiation 20 weeks before surgery. The hope is not only to increase the response to treatment, he said, but to “increase our accuracy in predicting who will respond.”

Multiplying approaches to colorectal cancer

Surgical oncologist Lily Lai, M.D., first had the hunch about FXR during her oncology fellowship training at City of Hope some 13 years ago.

At the time, little was known about FXR, short for farnesoid X receptor, except that it was heavily produced in the liver and intestines. FXR had only been cloned three years earlier by Barry M. Forman, M.D., Ph.D., now Ruth B. and Robert K. Lanman Chair in Gene Regulation and Drug Discovery Research at City of Hope.

Over the years, Lai pursued the protein, and today her suspicions have paid off. “At each step of our investigations, FXR seems relevant in cancer,” said Lai.

Scientists now know that FXR interacts with hormones and proteins to turn genes on and off. When she analyzed data from City of Hope patients, Lai found that people with higher levels of FXR in their colorectal tumors have a better chance of survival. In addition, patients with cancers that expressed the FXR protein lived longer with chemotherapy.

FXR, it seems, may both provide information about a patient’s prognosis and help guide physicians on how well a particular chemotherapy might work for a given patient. (For more about personalized medicine read Made 4U.)

In the laboratory, Lai showed that FXR can suppress colorectal cancer. Her team activated FXR using a bile acid, which binds to the receptor. This decreased the size and number of tumors seen in the intestines of mice by increasing cancer cell death.

Now Lai is conducting a phase I clinical trial on ursodiol — a bile acid already in use to dissolve gallstones — to determine its safety and dosing in patients with metastatic colorectal cancer.

FXR is unlikely to be a stand-alone cure because cancer growth is more complicated than that.

“No single approach will be a complete success,” Lai explained. “Cancer is tricky — it’ll do whatever it can to grow.”

She knows much remains to be learned about FXR. The ultimate goal, she said, will be to translate that knowledge into agents that work in concert with chemotherapy to improve treatment.

Joseph Kim