Engineering New Cancer-Fighting Drugs

Next-generation sequencing and advanced proteomic technologies are providing new insights into cancer patients’ individual malignancies and how particular characteristics impact cancer risk and treatment efficacy.
These insights make it possible for researchers to create new anticancer medications and treatment regimens tailored to a patient’s specific disease profile.

That is the mission of Cleveland Clinic Taussig Cancer Institute’s new cancer drug discovery program. The initiative, launched in 2013, intends to develop novel anticancer agents that target cancer specific abnormalities identified by the institute’s researchers. The program should produce more effective cancer medications and improve Cleveland Clinic patients’ access to experimental therapies.

Traditionally, drug discovery and development has been the domain of large pharmaceutical companies, whose priorities and timetables may differ from those of academic medical centers and their patients.
“Having a drug development enterprise within our own cancer center allows us to decide what to focus on, to set the agenda,” says Taussig Cancer Institute Chairman Brian J. Bolwell, MD, FACP. “I think we can develop important cancer drugs that change medical practice.”

“The drug discovery program helps us develop treatments that are specifically oriented to the patients our physicians are seeing in the clinic,” says Cleveland Clinic cancer researcher Jennifer Carew, PhD. “We make discoveries in specimens from patients who are being treated here, determine which targets may be therapeutically important, design compounds against those targets, and develop clinical trials to test them. We can get compounds faster from bench to bedside and improve patients’ access to clinical trials while learning more about which patients are likely to benefit.”

New Staff Bolsters Drug Discovery Effort

Dr. Carew, James Phillips, PhD, and their colleagues in Taussig Cancer Institute’s Department of Translational Hematology and Oncology Research (THOR) are currently leading drug discovery projects focused on the development of new, selective anticancer agents that inhibit the function of specific genes or proteins that cancer cells rely on to maintain their survival and resist the stress triggered by conventional chemotherapy.
Dr. Carew was recruited to join Cleveland Clinic earlier this year from the University of Texas Health Science Center, where she was Co-Director of Preclinical Research at the Institute for Drug Development. Dr. Phillips, who joined Cleveland Clinic in 2013, is a medicinal chemist with more than three decades of experience in the pharmaceutical and biotechnology industries. He currently holds 13 patents related to his work in drug development. Both researchers work under the guidance of THOR Chairman Jaroslaw Maciejewski, MD, PhD.

The starting point for the drug discovery process is the extraction and analysis of genetic and proteomic information from a patient’s tumor.

“I think that a personalized therapeutic approach is essential for the optimal development and application of targeted agents,” says Dr. Carew. “If we know the specific characteristics that are unique to a patient’s individual malignancy, we can develop novel drugs and treatment regimens that simultaneously target the most critical factors and pathways for improved selectivity and greater therapeutic benefit.”

“Dr. Carew and I collaborate on a very basic level,” says Dr. Phillips. “She will identify a particular protein or pathway that she thinks drives disease progression and/or drug resistance. I can then design compounds that antagonize their function based on what we know about the shape and function of those specific proteins.”

Tackling the Problem of Drug Resistance

One of their most advanced drug development efforts is focused on the generation of new agents that disrupt a protein degradation process called autophagy.

Dr. Carew and others have shown that some types of cancer cells activate autophagy to generate alternative sources of metabolic fuel. This fuel enables the cancer cells to survive the stress triggered by treatment with anticancer agents. Accordingly, autophagy functions as a mechanism of drug resistance.

Dr. Carew and her colleagues have shown that inhibiting autophagy increases the efficacy of a number of anticancer drugs in preclinical models. They translated these initial findings into an investigator-initiated Phase I clinical trial of the histone deacetylase inhibitor vorinostat in combination with the autophagy inhibitor hydroxychloroquine in patients with advanced solid tumors.

This study, sponsored by the National Cancer Institute, yielded encouraging results. Several patients experienced prolonged stable disease despite having relapsed following multiple lines of earlier therapy. One patient with advanced renal cell carcinoma with liver and lung metastases had a dramatic response and has remained active in the trial for more than four years. The results of this clinical trial along with five others that utilized hydroxychloroquine in combination with other anticancer agents to inhibit autophagy were published in the August 2014 issue of the journal Autophagy.

These findings are encouraging, but Dr. Carew thinks there is still significant room for improvement. “One of the most important things we learned during this initial clinical study was that doses of hydroxychloroquine that are well-tolerated by patients may not be completely inhibiting autophagic activity in tumor cells,” she says. “Newer agents that safely and more effectively disrupt the autophagy pathway are clearly needed. Dr. Phillips and I have been working closely to develop novel autophagy inhibitors, and we have some very interesting leads. We hope to be able to optimize one or more of these new compounds sufficiently so that they can be further tested in a clinical trial here at the Taussig Cancer Institute.”

Speeding Development and Improving Patients’ Access

Traditionally, Phase I clinical trials have only been used to establish a new compound’s safety, dosage range and side effects. But the knowledge that researchers gain during the drug discovery process may enable them to demonstrate some efficacy at this early stage too, potentially accelerating the compound’s development.

“If we can better understand from preclinical studies how a drug works and which specific types of cancer patients are likely to benefit from that type of drug, then we can focus clinical trial enrollment and future development on patients who have those characteristics,” Dr. Carew says. “Developing the compounds here means we can be sure that patients treated at the Taussig Cancer Institute have access as soon as the compounds are ready for clinical testing.”