Science

“Virtually all of the roughly half-million annual cancer deaths in the United States can be said to have occurred because chemotherapy failed. Such failures happen because patients’ tumors either were resistant at the outset or eventually developed resistance after exposure to the drugs.”

Tito Fojo, M.D., Ph.D.
Senior Investigator
National Cancer Institute’s Center for Cancer Research
Journal of the National Cancer Institute
Volume 95, Issue 4, Pp. 255-257(2003)

Twenty percent of newly diagnosed ovarian cancer patients will prove to be resistant to the most popular first-line chemotherapy agents and require second-line care within a few months of diagnosis.  Of the 80% that do respond, half or more will relapse within 24 months and also require second-line care. Ovarian cancer is not, however, the only cancer for which initial or later resistance is a serious treatment issue.  Resistance occurs in almost every form of cancer.  From brain cancer and breast cancer to prostate and many others, chemotherapy resistance is a concern to consider in almost every patient’s treatment plan.

Clearly chemotherapy resistance is one of the major obstacles to successful cancer care.  If resistance can be overcome, tumors can be treated and lives saved with existing chemotherapeutics. In some cases it might be possible to reduce side effects because reduced resistance may permit reduced doses of cytotoxic drugs.

Nature of Resistance

Chemotherapy resistance has been the subject of a number of studies. Xenobiotic response in cells is the main defense mechanism of the cell used to detoxify and remove cytotoxic molecules, including chemotherapeutics, from the cell. This system is responsible for much of the drug-resistance observed in cancer therapy.  The Keap1-Nrf-2 complex plays a critical role in regulating the cell’s protective response.  The Nrf-2 transcription factor affects many gene families and, among other things, produces direct antioxidants, encodes enzymes that directly inactivate oxidants, and enhances toxin export via the multidrug response transporters.  High constitutive expression of Nrf-2 was found in many types of drug-resistant cancers, creating an environment conducive for cancer cell survival.  Hence, inhibitors of Nrf-2 could potentially be used to block the xenobiotic response.  A decrease in drug detoxification and impairment of drug removal could result in drug-sensitivity and, therefore, enhanced efficacy of chemotherapeutic drugs. As noted in many recent publications, Nrf-2 mediated defense is a new area of intense research.  RTI has data clearly demonstrating that non-toxic RTI-79 inhibits several aspects of the xenobiotic response system by interfering with Nrf-2 response to certain chemotherapy agents.  Thus, this is a paradigm unlike other new cancer drugs that offer improved survival times but with increased toxicity.

The RTI Solution

Most chemotherapy-related research today focuses on the development of new cytotoxic compounds or the combination of multiple cytotoxic compounds into a new treatment regimen.  In RTI’s view, the major problem with these approaches is toxicity.  Increased use of more potent chemotherapy agents usually leads to increased side effects for patients.  These side effects may ultimately limit the amount of chemotherapy that can be used or diminish the patient’s quality of life.

We have discovered a class of compounds that effectively sensitize certain types of cancer cells to multiple chemotherapeutic agents. We have designed and synthesized approximately 125 RTI-x analogs and our first indication is the use of RTI-79 to sensitize drug-resistant ovarian cancer to DOXIL®. RTI-79 is the most potent and has the best pharmacological properties of the compounds studied. Initial PK and toxicity profiles in mice and dogs indicate that RTI-79 should not expose patients to new or increased toxicities.  Preliminary research has shown that RTI-79 materially interferes with the xenobiotic response system by decreasing the cellular levels of Nrf-2. In contrast to what we would anticipate if Nrf-2 were active, we see increased levels of reactive oxygen species in tumor cells and inhibition of Pglycoprotein pump activity. In essence, RTI-79 makes the cancer cell more sensitive to chemotherapy while increasing the accumulation of the chemotherapeutic in the cell.  Taken together, these actions make many of the cancer cell lines we have tested more susceptible to chemotherapy.