Ways To Teach Approved Drugs New Tricks: How To Combat Cancer

At the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, researchers present the results of some of these investigations, whether it is finding a new use for the immunosuppressant rapamycin or adapting the use of approved antibodies to reach the same targets within different cancers.

Combination of CP-751871, a human monoclonal antibody against the IGF-1 receptor, with rapamycin results in a highly effective therapy for xenografts derived from childhood sarcomas: Abstract C172.

Researchers at St. Jude Children's Research Hospital in Memphis, Tennessee, have discovered that an engineered antibody, in combination with rapamycin, may offer treatment for rhabdomyosarcoma, osteosarcoma, and Ewing's' sarcoma -- three rare childhood cancers. The antibody, called CP-751871, is currently in a Phase III trial by its developer, Pfizer, Inc., while rapamycin, an approved immunosuppressant, is also under study for its anti-cancer properties.

Combined, the researchers believe, the two therapeutics act in a way that helps to promote apoptosis, a series of internal signals within a cell that cause its self-destruction. CP-751871 binds to -- and thereby blocks the action of -- a cell surface protein called insulin-like growth factor receptor (IGF-1R), which research has shown to be a part of a process that limits apoptosis. Rapamycin has been shown to inhibit mTOR, a protein involved in regulation of cell growth, proliferation and survival. There is increasing evidence that activation of cellular proteins upstream or downstream of mTOR is critical in the process of cancer progression.

"Together, the two therapeutics seem to have a synergistic effect in human sarcomas, combined they function more strongly than either drug alone," said Raushan T. Kurmasheva, Ph.D., a post-doctoral fellow at St. Jude. "We are looking to extend our studies to include more sarcoma models, but we believe this looks like a promising clinical application for these drugs."

Ways to Teach Approved Drugs New Tricks

According to Kurmasheva, the combined therapy could be a breakthrough in treatment of human sarcomas in general and childhood sarcomas, in particular. Both Ewing's sarcoma and osteosarcoma are cancers of the bone and connecting tissue that are most frequently diagnosed in teens. Rhabdomyosarcoma is a rare disease that primarily affects children between the ages of one and five, but which can also strikes adolescents. While prognosis for childhood sarcomas is generally good, if caught early, children with these diseases face a grim prognosis if the cancer metastasizes, Kurmasheva says.

With support from the National Cancer Institute and Pfizer, the St. Jude researchers began their study in cell cultures of both cancer types. The antibody, alone, significantly retarded cell growth, they found. In animal models of sarcoma, both drugs curbed tumor growth. The two drugs combined, however, induced complete regression of established tumors. Due to the encouraging results, Kurmasheva and her colleagues are looking to expand their research to other animal models as well as look for biomarkers that could indicate positive response to treatment in a clinical setting.

Therapeutics for B-cell lymphomas

If one monoclonal antibody has revolutionized treatment of B-cell lymphoma, then two might offer even more benefit, according to researchers at Garden State Cancer Center based on their findings in preclinical animal studies.

The current standard of care is rituximab, a drug that targets CD20, a protein receptor that is highly expressed on the surface of lymphoma cells. Half of patients with B-cell lymphoma do not respond to rituximab, however, and those who do eventually relapse. Therefore, according to researchers, the search is on for other antibodies to add to rituximab to increase its efficacy.

Use of an agent called veltuzumab, an anti-CD20 antibody currently under development, along with milatuzumab, an experimental antibody that targets a different receptor called CD74, significantly improved survival in mice who received the monoclonal antibody treatment cocktail, the Garden State team reports. Using mouse models of B-cell lymphoma, they found that treatment with veltuzumab extended median survival time from 36 days in untreated mice to 70 days, and milatuzumab extended median survival time to about 90 days. However, when both agents were used, mice lived a median of 113 days.

"The important finding is that we show that using a combination of two antibodies targeting two different receptors on the malignant cells, when the receptors have different functions, leads to an improvement in survival over use of either antibody alone," said Rhona Stein, Ph.D., of the Center for Molecular Medicine and Immunology's Garden State Cancer Center.

"This also suggests that if the malignant cells become refractive to one antibody, the other may still be effective, since it can bind to a different receptor," she said.

Both veltuzumab and milatuzumab are "naked" antibodies monoclonal antibodies that are not bound to a therapeutic drug or radioisotope but each latches on to different receptors on the surface of lymphoma cells.

Milatuzumab binds to the CD74 receptor and is then rapidly internalized into the cell, in contrast to CD20, which is not taken inside cells as rapidly. "The CD74 receptor is known to process antigens as part of the immune response, and recently was shown to be a survival factor in certain malignant cells, chronic lymphocytic leukemia," she said. "So it appears to have a dual function, and the latter seems to make it an attractive candidate for antagonistic CD74 antibodies."

Veltuzumab is a second-generation humanized anti-CD20 antibody now in clinical testing, which works very similarly to rituximab, except that lower doses and shorter infusion times can be used, Stein says. Both of the drugs tested in this study, milatuzumab and veltuzumab, were developed by Immunomedics, Inc. Stein and her colleagues were funded through grants from the National Cancer Institute and the New Jersey Department of Health and Senior Services

These preclinical studies suggest benefit in testing the combination in patients, Stein says. "We believe that combination antibody therapy, just as combination chemotherapy, will be the future for antibody-based immunotherapy," she said.

Biomarker discovery

With the recent approval of four new agents and more coming through the drug development pipeline, treatment of advanced common kidney cancer has become a multiple choice decision of late but one without a definitive answer. Physicians say they have no rational way to decide which drugs or drug combinations would work best for patients with renal cell carcinoma, especially those whose cancer has recurred and spread.

Now, researchers at the University of North Carolina at Chapel Hill are adapting the idea of neoadjuvant therapy treating cancer before surgery to renal cell carcinoma. Their intent is to use a short course of treatment to evaluate the performance of the new drugs across populations of patients, and preliminary results are promising, the researchers say. Sorafenib, sunitinib, and temsirolimus were all approved for use in renal cell carcinoma within the last two years.

"Neoadjuvant therapy is an old idea, with the primary intent to downstage a tumor and increase the likelihood of successful surgical resection. We are using it to extract biomarker information on efficacy of treatment instead," said W. Kimryn Rathmell, M. D., Ph.D., of the Division of Hematology/Oncology at the Lineberger Comprehensive Cancer Center.

In this study, researchers measured patients' tumor responses to a short course of treatment before surgery using CT imaging, and analyzed potential biomarkers using functional imaging with PET imaging, blood and urine analysis before and after treatment, and the regulation of genes and proteins within the tumor.

Their first results, evaluating 4 to 8 weeks of sorafenib in 30 patients prior to surgery is currently under analysis. Early results show that among 10 of the 30 patients, the average response is a 10 percent reduction in size of the primary tumor, with a range between 0.8 percent and 28 percent. No tumor progression has been observed in any of the patients, and no unexpected surgical complications have been observed, Dr. Rathmell says.

Treating advanced renal cell carcinoma is difficult because results from clinical trials of new agents in advanced disease are difficult to interpret due to lack of good biomarkers, Dr. Rathmell says. "This is because there is limited access to tumor tissue acquired at or around the time of the treatment, the influence of prior therapy received by patients, and the relative co-morbidities these patients have compared to newly diagnosed patient," she said.

Additionally, no genetically engineered mouse models have been validated for renal cell carcinoma, Dr. Rathmell says. "Conventional xenograft studies, growing human tumor cells in an immunocompromised mouse fail to account for many of the tumor and host factors that influence tumor growth in humans, such as the absence of immune surveillance and an imperfect host environment for tumors," she said.

"The idea is to use a window of opportunity not traditionally explored to examine therapeutic biomarkers, and to identify subpopulations of patients who will derive a predictable higher likelihood of response from a given agent that is now available," Dr. Rathmell said. "Patients proceed to surgery regardless of the response to the very short course of treatment."

 Pancreatic cancer

Researchers at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center working in preclinical models of pancreatic cancer have found a way to identify those patients most likely to benefit from Tarceva (erlotinib), which has been approved for use in the disease but whose overall efficacy they seek to improve. Using a gene-expression-based tool to look for pathways involved in pancreatic cancer, they matched response to Tarceva to activation of the EGFR pathway which the drug targets.

"Identifying the subset of patients that benefits the most from Tarceva is a priority, and this method appears to offer us a way to do that," said Antonio Jimeno M.D, Ph.D., a researcher in the Gastrointestinal Cancer Program at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.

"Of course this is preliminary preclinical data, but the model we used is based on direct patient xenografts and not cell lines, and we have reasons to believe this system is more representative of cancer biology."

Many cancers rely on what scientists call "oncogene addiction," which refers to malignant processes that are driven by a single alteration, such as mutations in the EGFR gene in lung cancer or over-expression of HER2 in breast cancer. "Therapies have been successfully developed targeting those key alterations, turning the presence of the abnormality into a hallmark of activity, or a predictive biomarker," Dr. Jimeno said.

But the Hopkins researchers, led by Manuel Hidalgo, M.D., Ph.D., suspected that pancreatic cancer a disease in which EGFR-targeted therapies have proved to be of use, but where amplifications or mutations in the EGFR gene are rare is an example of a cancer driven by "pathway addiction." The problem, however, is that no one knows what the determinant of Tarceva activity is in pancreatic cancer, Jimeno says.

The team used a tool known as gene set enrichment analysis (GSEA), which classifies 25,000 genes assayed in a chip into 198 predetermined pathways, be they metabolic, structural, or signal transduction. This analysis was conducted by Aik Choon Tan, Ph.D., from the Institute of Computational Medicine at Johns Hopkins. The researchers looked at messenger RNA levels to determine which pathways were more actively expressed in patients whose disease responded to Tarceva. Two of the most frequently expressed pathways in Tarceva-sensitive cases were the closely related EGFR and MAPK pathways, they found.

"What we did that was different is that rather than examining gene expression datasets looking for outliers or individual genes, we employed GSEA to detect modest but coordinated changes in expression of genes involved in a common pathway or biological function," Dr. Jimeno said.

They then validated the prediction in a prospective cohort of patient-derived tumors xenografted on mice that were treated with Tarceva, and found that the EGFR pathway was again highly expressed in Tarceva-sensitive tumors compared to resistant tumors, and the EGFR pathway signature predicted anti-EGFR treatment response in this second group of tumors.

"We are excited because this reinforces the notion that targeted agents work in cases where the target is relevant," Dr. Jimeno said. "We only need to take into consideration the enormous intricacy of cancer and use tools that permit us to factor in that complexity."

Dr. Jimeno adds this finding offers some good news in this difficult-to-treat cancer. "GSEA or another tool like it might help us down the road to tailor anti-EGFR therapy to those patients most sensitive to it, and it also provides an alternative, more integrative way to think about how to look for pathways that are relevant in cancer," he said.

Dr. Jimeno and his colleagues were supported in part by an American Society of Clinical Oncology Young Investigator Award to Antonio Jimeno, the Sol Goldman Center for Pancreatic Cancer Research, the Viragh Family Foundation and the Lee family.