Public Release: 

Three molecular-targeted compounds show promise against cancers

American Association for Cancer Research

BOSTON (November 20, 2003) -- Early clinical studies show that a new generation of drugs that target signaling pathways -- the internal channels through which cancer cell growth is controlled -- and the body's own production of tumor-suppressing proteins hold promise for the treatment of a variety of tumors. Patient trials evaluated drug tolerance and potential anti-tumor activity against a variety of cancers such as renal cell, colorectal and non-Hodgkin's lymphoma of three compounds. The studies were presented today at the International Conference on Molecular Targets and Cancer Therapeutics organized by the American Association of Cancer Research (AACR), National Cancer Institute (NCI) and European Organization for Research and Treatment of Cancer (EORTC) in Boston.

Phase II study of SU11248 in patients with advanced malignancies incorporating PET imaging: Abstract 663

An experimental pill aimed at several important signaling molecules involved in angiogenesis and cell growth produced evidence of tumor shrinkage and arrest in tumor growth in patients with advanced, refractory cancers. Dr. Guy C. Toner, Centre for Developmental Cancer Therapeutics in Melbourne, Australia, presented preliminary results from 41 patients in the clinical study.

The compound, called SU11248, inhibits signaling proteins called tyrosine kinases, which help tumor cells, its surrounding cells, and blood vessels that feed them, grow. Specifically, SU11248 is designed to target three important kinases - VEGFR, PDGFR and KIT.

"The study employed an imaging technique, called PET scanning, to assess biological response and correlated the results with conventional responses and with known angiogenesis biomarkers, such as circulating sVEGF," said Dr. Toner.

The study enrolled patients with a variety of tumor types, including colorectal, sarcoma, melanoma, and renal cancers that were refractory to standard therapies. SU11248 was administered as a tablet, once daily for four weeks followed by a two-week break. The main study period comprised two of these cycles of therapy over a period of 12 weeks. Those patients considered by their doctor to be benefiting from therapy were allowed to continue on treatment.

Two patients had a major response to therapy assessed by the degree of shrinkage of tumors. A further 15 patients had benefit defined as no progression of their cancer and continued therapy beyond the 12 week study period. Most of these patients had improved symptoms or reduced tumor activity demonstrated on PET scan. Some also had significant tumor shrinkage that was less than required to meet the criteria for major response.

The most common side effects were lethargy, low blood counts, and gastrointestinal symptoms. Almost all patients reported some side effects and delays in treatment and reductions in dose were relatively common. An uncommon side effect was observed in some patients who developed loss of pigmentation in their hair while receiving treatment.

"Both PET response and clinical benefit have been seen in patients with a range of malignancies," said Dr. Toner. "These preliminary results confirm the promise of this therapeutic approach."

Phase I clinical trial of an oral histone deacetylase inhibitor: suberoylanilide hydroxamic acid (SAHA): Abstract 1000

Some patients with advanced solid tumors and hematologic malignancies experienced measurable reductions in their disease when offered the pill form of an experimental compound that alters certain genetic patterns of cells. Researchers at Memorial Sloan Kettering Cancer Center led the first-ever human study of this pill in a 60-patient, Phase I study of the compound called suberoylanilide hydroxamic acid or SAHA.

"The results of our clinical trial demonstrate that this novel treatment has significant anti-tumor activity in a variety of advanced cancers that were resistant to previous therapy," said the study's lead author William Kelly, DO, a medical oncologist at MSKCC. "The results support the further investigation of this molecule in additional trials."

SAHA is designed to work by inhibiting an enzyme, called histone deacetylase, that functions as "glue" to keep DNA tightly wrapped around proteins called histones, and inactive. When SAHA binds to histone deacetylase, DNA becomes unwrapped from the histone core, freeing the genes in a DNA chain to be turned on, or "expressed."

Pre-clinical studies have shown that the drug can decrease and inhibit the growth of many tumors in the laboratory. SAHA has been given safely to other patients intravenously, but this is the first study evaluating a pill form of the drug. This approach to treating cancer was developed by MSKCC study co-authors Drs. Paul Marks, MD, and Richard Rifkind, MD, and their colleagues.

In the clinical study reported at the meeting, researchers evaluated three escalating dosing schedules of SAHA in 60 patients. Blood tests confirmed that the drug successfully hit its molecular target (histone deacetylase), as it did in previous laboratory studies. Study investigators reported a reduction in measurable disease among some patients with solid tumors as well as hematologic malignancies (including one complete remission.) Major side effects included anorexia, dehydration, diarrhea, and fatigue however the effects subsided quickly after the patients stopped taking the drug.

A Phase II study of BAY 43-9006 using the randomized discontinuation design in patients with advanced refractory cancer: Abstract 1176

An experimental drug targeted at an enzyme that regulates tumor proliferation may provide a significant benefit for patients with advanced and progressive renal cell cancer, the most common form of kidney cancer. In this five-center study, 44 percent (18 of 41) of patients had tumor shrinkage of at least 25 percent within 12 weeks of treatment, according to researchers from the University of Chicago. Another 29 percent (12 patients) had their tumors stabilize within 25 percent of pre-treatment size. The remaining 27 percent (11 patients) left the study because of progressive disease or adverse effects, such as a painful rash or digestive problems.

The drug, called BAY 43-9006, is believed to inhibit an enzyme, known as Raf kinase. The Raf kinase enzyme regulates tumor-cell proliferation and may also play a role in the growth of new blood vessels to feed the tumor.

"The frequency of tumor shrinkage and disease stabilization is quite encouraging," said the study's lead investigator, Mark Ratain, M.D., professor of medicine at the University of Chicago. "All patients in this study had progressive disease that did not respond to at least one prior systemic treatment. The benefits observed in this trial suggest that BAY 43-9006 has exciting potential for this patient population."

Median survival for patients with advanced metastatic kidney cancer is less than one year. Fewer than 10 percent of patients with advanced kidney cancer respond to chemotherapy. Response to immunotherapies such as IL-2 can be slightly higher, around 15 percent, but with considerable toxicity.


Founded in 1907, the American Association for Cancer Research is a professional society of more than 21,000 laboratory, translational, and clinical scientists engaged in cancer research in the United States and in more than 60 other countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication, and advocacy. This work is carried out through five major peer-reviewed scientific journals and high-quality scientific programs focusing on the latest developments in all areas of cancer research.

The National Cancer Institute, founded in 1971, is the principal United States government agency charged with coordinating the National Cancer Program. It facilitates international cooperation in clinical trials involving U.S. and foreign collaborating institutions.

The European Organisation for Research and Treatment of Cancer was organized in 1962 to conduct, develop, coordinate and stimulate laboratory and clinical research in Europe, and to improve the management of cancer and related problems by increasing the survival and quality of life for patients.

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