New Promising Strategy for Cancer Therapy Offers Hope For Patients

Cancer research at UC Irvine has breached another forefront.

Associate Professor in the Departments of Molecular Biology and Biochemistry and Associate Director of the Institute for Immunology, David Fruman and colleagues successfully used a new class of chemical compounds to effectively kill leukemia cells.

The research team learned about this compound, PP242, through their collaboration with Kevan Shokat, Ph.D. at UC San Francisco.

PP242 eliminates leukemia cells by inhibiting the enzymatic activity of mTOR.

Fruman explains why this inhibitory effect is significant.

“The enzyme mTOR is highly active in nearly all cancer cells, including leukemia cells. It is required for speeding up protein synthesis and other anabolic activities in preparation for cell division,” Fruman said.

Unlike drugs currently used, PP242 is well-tolerated by normal blood cells with notably weaker effects on the cell’s ability to function and proliferate.

Matthew Janes, a graduate student researcher in the Departments of Molecular Biology and Biochemistry, helped design, oversee and perform most of the experiments in the manuscript.

“We modeled a particular form of leukemia that is driven by abnormal activation of a normal signaling pathway. This pathway is central to integrate signals from growth factors, nutrients, stress to regulate cell growth and proliferation. It is essentially conserved from all mammals to flies, and even yeast,” Janes said.

Taking their findings a step further to the clinical level, Fruman and his colleagues have collaborated with the pharmaceutical company Intellikine.

Janes discussed in detail what this entails.

“Intellikine has developed small molecule inhibitors to target the signaling pathway. They are currently running a clinical trial investigating a similar ‘analog’ of the drug we used in our study. Our collaboration involves using their drugs to study their effects in our disease model of expertise, leukemia,” Janes said.

To qualify to participate in the focus group for the clinical study, individuals need to fulfill certain criteria.

Fruman defined what these requirements are.

“The first phase of clinical trials will be open to patients with advanced solid tumors. The purpose of phase one is to determine whether the compounds are safe and what the maximum tolerated dose is in humans. If the compound passes to later phases of development, the main goal will be to determine efficacy in a variety of different cancer settings – possibly including leukemia,” Fruman said.

From the study, Fruman hopes people will recognize that it is possible to selectively destroy leukemia cells while leaving normal immune cells relatively unharmed.

Likewise, Janes hopes that people will understand that efforts are being made to improve current cancer therapies. He noted that while current non-targeted chemotherapies are devastating and toxic, research in this field has uncovered more selective avenues to target cancer cells.

This study has been published online in the biomedical research journal, Nature Medicine.

Also assisting in this study were graduate student Jose Limon and undergraduate students Raymond Lim and Melissa Chavez. The latter two were a part of the June 2009 graduating class.

Fruman and his colleagues have intentions to further investigate this specific topic. They will attempt to understand more about why the compounds selectively kill leukemia cells and whether their findings have a more general application to other types of cancer.