Weill Cornell Medical College researchers have devised an innovative boxer-like strategy, based on the serial use of two anti-cancer drugs, to deliver a one-two punch to first weaken the defenses of multiple myeloma and then deliver the final knock-out punch to win the fight.
The study, published online by the journal Blood, is the first to show that precise timing of therapies that target a cancer cell's cycle — the life phases leading to its division and replication — disables key survival genes, resulting in cell death. The drug that delivers the weakening jab at the cell cycle is the experimental agent PD 0332991, which allows bortezomib, a proteasome inhibitor already approved for use in myeloma and lymphoma, to land the final defeating blow at lower than normal doses.
While this is potentially good news for patients with multiple myeloma, a cancer of blood plasma cells that is currently incurable, the study suggests that using this therapeutic strategy could also work for other tumor types, says the study's senior investigator, Dr. Selina Chen-Kiang, professor of Pathology and Laboratory Medicine and of Microbiology and Immunology at Weill Cornell Medical College.
"Because robust functioning of the cell cycle is crucial to cancer growth and survival, this mechanism-based strategy could theoretically be used against many kinds of cancers," she says.
"Based on the genetics of a patient's tumor, we could pair PD 0332991 with the right cytotoxic partner drug to both inhibit cancer cell division and sensitize the cells for that knock-out punch," says Dr. Chen-Kiang. "We are very excited about the promise of this approach."
In fact, physicians at Weill Cornell have opened two new human clinical trials, one in multiple myeloma and one in mantle cell lymphoma, based on the findings of this study in a mouse model as well as on a previous phase I clinical trial led by Weill Cornell investigators that tested PD 0332991 in patients with mantle cell lymphoma.
Playing Havoc with the Cancer Cell Cycle
Dr. Chen-Kiang and her laboratory colleagues have long studied genes and proteins that control the cell cycle and cell suicide (apoptosis) in cancer. Cancer is fundamentally a disease of uncontrolled cell proliferation, where cells are able to continuously divide. In contrast, cell division in a healthy individual is regulated by the cell cycle, an orderly sequence of programmed gene expression in which the cell is driven through various checkpoints by a highly regulated network of proteins.
Cyclin-dependent kinases (CDKs) are molecules that power the progression of the cell cycle through its four phases. For example, CDK4 and CDK6 help move cells through the first G1 "gap" phase to later phases where the cell splits in two. In many cancers, these two enzymes are over-expressed, ensuring continual growth. Therefore, targeting CDK4 and CDK6 to shut them down has long been a goal of cancer drug discovery, but clinical success, so far, has been disappointing because of lack of effectiveness as well as drug toxicity, says Dr. Chen-Kiang.
PD 0332991, a small molecule synthesized by Pfizer, is different because it is exceptionally selective for CDK4 and CDK6, she says. The drug initially did not receive much attention because it is also reversible, meaning that it needs to be used continuously to inhibit CDK4 and CDK6; withdrawing it would reactivate these enzymes, stimulating growth.
But Dr. Chen-Kiang had been searching for a drug that she could use for her selective cell cycle-based therapy — the idea being that playing havoc with a cancer cell's cycle would fatally weaken it when more traditional anti-cancer drugs are used sequentially.