NIH Supports Researcher’s Work Toward a Nontoxic Cancer Fighter

If cancer doesn’t make you sick enough, cancer drugs can make you feel sicker.

In 30-plus-years as a cancer researcher at Duquesne, Dr. Aleem Gangjee has kept concerns about the toxicity of cancer medications and their impact upon normal cells top-of-mind.

So Gangjee is understandably happy that, amid sequestered and reduced federal funding, he has received a $1.56 million, three-year R01 grant from the National Institutes of Health’s National Cancer Institute to further develop his latest compounds, which promise not to harm normal cells.

Gangjee’s research title sounds very clinical and complicated—Purine Synthesis Inhibitors With Selective Folate Receptor Tumor Transport. But for anyone who has faced cancer or watched a friend or loved one struggle against the disease, Gangjee’s work makes the pulse quicken.

Growth is at the root of cancer’s harsh impact, and DNA is at the root of cell growth. So Gangjee has chosen to develop compounds that target the basic building blocks of cancer cells’ DNA.  That thought alone is not new. “There are several drugs that try to inhibit synthesis of DNA,” Gangjee said. “But they are extremely toxic.”

He wanted his compounds to be more selective—so selective, in fact, that they would impact cancer cells alone, not normal cells. To do so, Gangjee focused on a specific system, called a transport system that is expressed only in select tumor cells. The system is not expressed in normal cells, so the mechanism itself precludes toxicity.

This folate receptor alpha transport system shuttles chemicals from outside cancer cells to the inside of the cells, carrying Gangjee’s tumor-fighting compounds like a Trojan horse, fighting cancer from the inside out. Additionally, his compounds fall into a category of “targeted therapies:” compounds that target cancer cells predominately—or exclusively—over normal cells.

These compounds hitch a ride on a transport system special to certain types of ovarian, breast, liver, lung and colon cancers. Once they gain entry to the cancer cells, they selectively block the signaling systems involved in synthesizing DNA.

“To our knowledge, this is the only type of targeted therapy that deals with transport into tumor cells using a folate transporter,” Gangjee said. “The killing mechanism in these cells brings another advantage, that is, the compounds indirectly inhibit the signaling machinery called mTOR,” the pathway that handles cellular 9-1-1 calls regarding damage, growth and nutrition.

The mTOR pathway, Gangjee said, is established for treating cancer. But by acting on two different levels, Gangjee’s subversive compounds pack a double whammy for cancers. Plus, because multiple mechanisms are involved, cancer cells are not likely to become resistant to the treatment, as they might if this were a single-pronged attack.

“It is wonderfully selective, exquisitely selective and very, very potent,” said Gangjee, who previously had used a different transporter as his Trojan horse. “The beauty is we do this selectively in tumor cells only, because our drugs don’t get into the normal cells.”