Bench to Bedside: How to Fast Track Targeted Cancer Drugs with Radiation into the Clinic

Researchers from the translational research program of the National Cancer Institute and the Radiation Therapy Oncology Therapy Group have developed new guidelines to help fast track the clinical development of targeted cancer drugs in combination with radiation therapy.

The suggested strategic guidelines, published in the Journal of the National Cancer Institute in a recent commentary with lead author Yaacov Richard Lawrence, MRCP, an adjunct Assistant Professor in the Department of Radiation Oncology at Thomas Jefferson University and Director of the Center for Translational Research in Radiation Oncology at Sheba Medical Center in Israel, offers specific steps in the preclinical and early phase clinical trial process to get well-studied and novel targeted agents into the clinic more quickly.

Over the last decade, molecular agents that target cellular survival and growth, like Erlotinib and Sunitinib, have been developed but alone have had modest effect on improved survival. Combining such targeted agents with radiation therapy, however, has the potential to improve cure rates and long-term overall survival.

“There’s a missed opportunity in today’s cancer care treatment,” says Dr. Lawrence. “There is very promising laboratory data out there, but the clinical development of these new drugs with radiation has been limited. Here, we have put together a road map to help overcome obstacles and speed the development of new pipeline drugs with radiation.”

Adding radiation therapy to existing chemotherapy agents to radiation therapy has improved survival, and the authors of the commentary, which includes Adam P. Dicker, Chair of the Department of Radiation Oncology at Jefferson, believe new targeted therapies can follow in the same path.

“We know we want to repeat that success with new biological drugs,” says Dr. Lawrence. “In order to do that, we need direction, which is sorely lacking. These guidelines explicitly explain how much evidence is needed to go forward from the lab into the clinic, and furthermore how to design the clinical trials in humans.”

The guidelines discuss key questions when investigating specific targeted agents and tumor types, designing new clinical trials, such as the ‘time-to-event continual reassessment method design’ for phase I trials, and randomized phase II “screening” trials, and the use of surrogate endpoints, such as pathological response.

It also discusses the role and purpose of preclinical studies in radiation oncology drug development and how to identify new, radiation response agents.

There are challenges to drug development with radiation, the authors explain. A major problem is the limited interest from the pharmaceutical industry in developing drugs with radiation, which is of special importance since the pharmaceutical industry fund a large amount of clinical cancer research. Furthermore, significant individual skills and institutional commitments are also required to ensure a successful program. The situation has been extenuated by the decrease in radiation biologists in recent years.

It is hoped that by providing a clear pathway, the guidelines will help the field overcome these barriers and create a focus and interest in drug development.
Some new approaches, the researchers say, include combining radiosensitizers with hypofractionated (high daily dose) radiation schedules and integrating immunomodulators with radiation therapy.

“We feel passionate that a a good way to push clinical care forward for cancer patients is by combining these two types of treatment: advanced radiation treatment together with the new generation of anticancer drugs,” says Dr. Lawrence. “We know where the future lies, and guidelines provide the path to bring us there.”

The full guidelines in the JNCI can be found here: http://jnci.oxfordjournals.org/content/early/2012/12/07/jnci.djs472.full



NCI Awards ‘Provocative Questions’ Grant to Thomas Jefferson University Researcher Scott Waldman

Scott Waldman, M.D., Ph.D., chairman of the Department of Pharmacology and Experimental Therapeutics

Scott Waldman, M.D., Ph.D., chairman of the Department of Pharmacology and Experimental Therapeutics at Thomas Jefferson University, has been awarded one of the prestigious “Provocative Questions”  grants from the National Cancer Institute (NCI) , as part of the Institute’s ambitious program to tackle the “important but not obvious” questions in cancer to ensure no stone was left unturned  after decades of promising research.

Scientists have known for a long time that obesity contributes to cancer risk, but they don’t know why.

That’s one of the questions set forth by the NCI—24 in total—that Dr. Waldman will help answer with a four-year grant for almost $1.2 million. Out of 700 applicants, just 57 recipients from institutions nationwide were chosen.

For Dr. Waldman, the answers behind cancer and obesity may lie in a hormone receptor known as guanylyl cyclase C (GCC), found mostly in the intestinal tract.

GCC has been established as a suppressor of colorectal cancer tumors and a useful tool to better predict colon cancer risk and recurrence by Dr. Waldman and his team. Preclinical and clinical studies found that lower levels of GCC were associated with an increased risk for colorectal cancer. They also discovered administering GCC reversed that trend.

More recent studies have revealed GCC’s role in appetite. The researchers found that silencing GCC affected appetite in mice, disrupting satiation and inducing obesity. Conversely, mice who expressed the hormone receptor knew when to call it quits at mealtime.

Now, under the “Provocative Questions” program, Dr. Waldman will further explore the relationship between cancer and the hormones regulating GCC to get a deeper understanding of the mechanisms of the risk posed by obesity—and a possible therapeutic target to treat it.

This is a promising notion, given that one-third of the U.S. population is considered obese, and that obese people have a 50 percent increased risk of being diagnosed with colorectal cancer.

“We are proposing that obesity increases colorectal cancer risk by suppressing the expression of those hormones, and silencing GCC,” said Dr. Waldman, “which is an effect that can be reversed by dietary calorie restriction or oral GCC hormone replacement therapy.”

There is potential for immediate translation of results to help reduce colorectal cancer risk in obese patients, given that an oral GCC drug to treat constipation just received regulatory approval, added Dr. Waldman, who is a member of Jefferson’s Kimmel Cancer Center.

The Provocative Questions project emerged from discussion among a number of veteran cancer researchers that noticed there were many questions — some important but not very obvious, some that had been asked but abandoned in the past because there were no ways to study or address them, some sparked by new discoveries or novel technologies — that could stimulate the NCI’s research communities to use laboratory, clinical, and population sciences in especially effective and imaginative ways.

More than 50 grants, attempting to answer 20 of the 24 proposed questions, with $22 million are being funded this year from that set of applications.

This research is supported by the National Cancer Institute of the National Institutes of Health under award number R01CA170533-01.



Jefferson Clinical Trial: Can a Cholesterol Drug Prevent Colon Cancer?

Thomas Jefferson University has started recruiting patients for a new National Cancer Institute (NCI)-sponsored clinical trial to test whether the cholesterol-reducing drug rosuvastatin is effective in the prevention of recurrent colon cancer.

Previous laboratory research and population studies have shown that patients taking statins, the class of drugs that lowers cholesterol, had fewer colon polyps, which can lead to cancer if left untreated. However, those findings come largely from retrospective, observational studies originally designed to investigate lipid-lowering or cardiovascular endpoints in the short term rather than tumor endpoints.

“The jury is still out, and we need to get definitive answers,” said Bruce Boman, M.D., Ph.D, professor of medical oncology at Thomas Jefferson University and principal investigator for the national clinical trial. “This prospective design comparing a statin against a placebo is what is needed to address the question: Are statins effective chemoprevention agents or not?”

This five-year, nationwide study will be the first randomized, prospective, placebo-controlled, double-blind study to evaluate the drug’s role in preventing colon cancer and will involve 1,740 patients in total.

Conducted by a network of cancer research professionals from the National Surgical Adjuvant Breast and Bowel Project (NSABP) at 400 medical centers across North America, including Jefferson, the study involves patients who have recently been diagnosed with early stage colon cancer, and who were not already taking statins for high cholesterol.  Those recruited have been surgically treated for stage I and II colon cancers previously.

Patients will be randomly assigned to one of two groups.  Each group will take one pill a day for five years.  One group will receive rosuvastatin, while the other group will receive a placebo.

The cumulative incidence for developing colorectal adenomas three years after surgery/treatment for early stage colon cancer is 50 percent. Thus, the benefit/risk ratio for chemoprevention intervention is potentially very positive in this high-risk population.

“There will be an estimated 102,900 new cases of colon cancer in the United States this year,” said Norman Wolmark, M.D., NSABP’s chairman.  “In fact, colorectal cancer is the third most common cancer found in men and women in this country.   We hope this trial will be an important step in reducing these numbers.”

The principal investigator for the trial at Jefferson is Scott Goldstein, M.D, director of the Division of Colon and Rectal Surgery at Thomas Jefferson University.

People recently diagnosed with a Stage I or II colon cancer and interested in the study should contact Vicki Squire of Thomas Jefferson University at  Vicki.Squire@jeffersonhospital.org or 215-503-5641.

A list of other sites in North America that are participating in the study may be found at http://www.nsabp.pitt.edu/P5_Sites.asp