A pancreatic cancer drug discovered in professors Paul Bingham and Zuzana Zachar’s lab in the Department of Biochemistry and Cell Biology at Stony Brook University has now entered Phase III, or multi-center testing stage.
During the multi-center testing stage, the drug will be tested among qualifying patients in clinical research centers nationwide, including Stony Brook Cancer Center. The trial will use a combination of FOLFIRINOX and CPI-613 — a partial inhibitor of the tricarboxylic acid (TCA) cycle, a pathway used in the mitochondria for glucose metabolism — in metastatic pancreatic cancer patients. Dr. Minsig Choi, an attending physician who specializes in gastrointestinal medical oncology, is the principal investigator of the trial.
FOLFIRINOX is a chemotherapy regimen that uses multiple drugs to kill cancer cells. The use of CPI-613, a lipoate analog — a chemically equivalent compound similar to one of the intermediates in the TCA cycle — may increase the vulnerability of cancer cells to traditional chemotherapy regimens by inhibiting cancer cells’ almost “addictive” use of the TCA cycle, Choi explained. Thus, combinational therapy may improve life expectancy for patients.
“While normal cells can use other pathways when the TCA cycle is inhibited, cancer cells are more sensitive to changes in the TCA cycle,” Choi said.
According to Choi, metastatic pancreatic cancer is one of the most difficult forms of cancer to tackle. Stage one and stage two pancreatic cancer can often be treated surgically and followed with chemotherapy regimens. Patients who forgo treatment live up to three months after a diagnosis has been made. According to Columbia University’s Pancreas Center website, the percentage of patients with metastatic pancreatic cancer who live past five years sits at 2.4%.
With traditional chemotherapy regimens, patients can live up to one year. However, Phase I and Phase II clinical trial results of FOLFIRINOX and CPI-613 has pushed patient life expectancy past the 20-month mark, post initial diagnosis, according to Choi.
“The Phase I/II trial had 17 evaluable patients,” Bingham wrote in an email. “Though this is a relatively small number, the effects were so large that we had adequate statistical power to motivate the Phase III trials now underway.”
To advance a drug to Phase III status is no simple task. Decades of bench research showing the efficacy and potency of a drug are often required before a drug can be developed for clinical trials. CPI-613’s discovery can be traced back to Bingham and Zachar’s laboratory. Having worked for the past 18-20 years in the field of cancer research, their last seven years heavily focused on discovering the mechanisms behind CPI-613.
According to Bingham, finding ways to preferentially kill cancer cells over normal cells can be quite difficult. The mitochondria — an organelle within cells that metabolizes glucose, among other things — houses many metabolic pathways that can potentially be targeted.
CPI-613, an inhibitor of a key enzyme in the TCA cycle, can be used to “lie to this machinery, making it think that there is too much carbon going through the enzyme and that it should shut the enzyme off,” Bingham said.
By inhibiting the TCA cycle, many other metabolic pathways that use this cycle cease to function, thus shutting down mitochondrial metabolism.
“Attacking the TCA cycle in this way is a uniquely potent way to attack cancer metabolism,” Bingham said. “CPI-613 is preferential in attacking tumor cell mitochondria, while mostly leaving normal mitochondria alone.”
Dr. Jingfang Ju of the Pathology Department at the Renaissance School of Medicine, who has spent the last decade in cancer research, agrees that this approach may be effective.
“Cancer cells are addicted to glucose more so than normal cells,” he said. “That creates a therapeutic window. Thus, you can preferentially eliminate cancer cells and normal cells. However, there is potential for some normal cells to be impacted.”
Ju’s laboratory uses technology to manipulate microRNA, or double stranded RNA, which can modulate a host of gene targets within the cell. Modulation can include increasing or suppressing the activity of genes that have been implicated in cancer. His lab has demonstrated that manipulating the code of microRNA to target genes involved in cancer can be both potent and effective in reducing the toxicity of cancer in a mouse model. The Ju lab’s microRNA technology has been licensed to Curamir Therapeutics, which will develop the drug for further testing in patients.
Both Ju and Bingham have advanced a drug from discovery at the lab bench to pharmaceutical development. According to the Association of Medical Colleges’ website, basic scientists provide the foundational knowledge which lies at the crux of solving real-life problems, — like cancer.
“This is a dream for basic scientists,” Ju said. “We work on research. Our ultimate dream is to impact patient care.”
Bingham expressed a similar line of thought.
“As a basic scientist, you hope that what you do may impact human welfare,” he said. “I still remember when I met the first patients whose lives were prolonged by [CPI-613]. It was pretty amazing.”
Though pancreatic cancer is fatal, extending life expectancy may mean a mother getting to see her daughter walk down the aisle on her wedding, Choi said, recounting one of his patients’ experiences.
“To young people, extending life for six or eight months may be just another number, but for the actual physician taking care of that patient, that small number could still mean a lot [for patients],” Choi said.
“If this drug is effective in pancreatic cancer, it’s going to be very effective in other diseases as well, including colon cancer, breast cancer, prostate cancer,” Choi said. “The potential for this drug is pretty good.”
Ju agreed with this assessment.
“It’s very possible that this treatment, if successful, can be translated to other tumor types,” he said.