A new study conducted by researchers from Weill Cornell Medical College reveals that precise timing of cell’s cycle targeting cancer therapies disable key survival genes and lead to cell death.
The study, published online in the journal Blood, shows that researchers have come up with a unique strategy of using two anti-cancer drugs in a series, similar to a combination of boxing punches. Whilst the first drug, the experimental agent PD 033299, delivers the first punch to weaken the defenses of multiple myeloma, the second drug, bortezomib, delivers the final knock-out punch. Bortezomib is a proteasome inhibitor that is already approved for the treatment of myeloma and lymphoma.
Senior researcher Dr. Selina Chen-Kiang, professor of Pathology and Laboratory Medicine and of Microbiology and Immunology at Weill Cornell Medical College, says that this innovative strategy could potentially not only be great news for patients with multiple myeloma, an incurable cancer of blood plasma cells, it may also work for those with other tumor types.
Chen-Kiang says:
“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. 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 knockout punch. We are very excited about the promise of this approach.”
Based on the findings of this mouse model study and on an earlier Phase I clinical trial that assessed PD 0332991 in patients with mantle cell lymphoma, the Weill Cornell researchers have started two new human clinical trials, one in multiple myeloma and one in mantle cell lymphoma.
Dr. Chen-Kiang and her team have been researching genes and proteins that control the cell cycle and cell suicide (apoptosis) in cancer for some time. In healthy people for instance, cell division is controlled by the cell cycle, an orderly sequence of programmed gene expression in which a tightly controlled network of proteins drives the cells through various checkpoints, whereas the cells in cancer patients proliferate uncontrollably and can divide continuously.
The progression of the cell cycle occurs in four phases that are powered by cyclin-dependent kinases (CDKs) molecules. For instance, CDK4 and CDK6 assist the cells to move through the first G1 ‘gap’ to the next phase, in which the cell divides into two. Given that CDK4 and CDK6 are overexpressed in numerous cancers and therefore ensure continual growth, scientists have long been trying to develop drugs to target these two molecules to block their activity. However, Chen-Kiang says that so far, there have not been any clinical successes due to lack of efficacy and drug toxicity.
She states that the small molecule PD 0332991 synthesized by Pfizer is different due to its exceptional selectivity for CDK4 and CDK6, but that the drug initially failed to create sufficient attention due to its reversibility, meaning that it needs to be used continuously to block these two molecules. If PD 0332991 is withdrawn, these enzymes would be reactivated and promote growth.
However, Dr. Chen-Kiang tried to develop a drug that could be used for her selective cell cycle-based therapy, which is based on her theory that if cancer cell’s cycles would be adequately interrupted, they would be weakened to the point of the cells dying, whilst traditional anti-cancer drugs are used sequentially.
She explains:
“Given that the gene expression program is coupled to the cell cycle, we hypothesize that inhibition of CDK4/CDK6 maintains gene expression programmed for early G1, while preventing the expression of genes scheduled for other cell cycle phases. And because metabolic needs in tumor cells differ from normal cells, this prolonged arrest in G1 would create an imbalance in gene expression that preferentially sensitizes tumor cells to cytotoxic drugs, allowing for low-dosage treatments.”
She continues saying: “Because PD 0332991 is also reversible, we further hypothesize that release from G1 by removal of the inhibitor would synchronize the cell cycles, but may not synchronize gene expression schedules. This tension between cell cycle synchronization and differential gene expression synchronization further weakens the tumor cells during their progression, as does the heightened metabolic load and demand for energy to replicate DNA.”
Chen-Kiang’s hypothesis was confirmed by the study. They discovered that using PD 0332991 sensitized the cells to being destroyed through bortezomib by inducing a prolonged arrest of G1 and subsequently releasing it again. This was confirmed in laboratory studies in mice and in myeloma tumor cells that were left with healthy bone marrow cells.
First author Dr. Xiangao Huang, assistant research professor of Pathology and Laboratory Medicine at Weill Cornell Medical College comments: “We found bortezomib, even when used in a low dose, was significantly more effective when the cancer cells were sensitized by our strategy.”
When the researchers investigated this mechanism, they found that prolonged arrest in G1 significantly enhanced cell suicide induced by bortezomib because the cell loses the crucial IRF4 protein during this phase, that is necessary for the myeloma cells’ survival, and it gains several pro-apoptotic proteins.
Dr. Chen-Kiang concludes:
“These findings demonstrate for the first time that key survival and apoptotic genes are regulated by the cell cycle in cancer cells, and suggest new molecular targets for intervention. This work represents the seamless integration of basic biological research on the cell cycle and direct medical application in clinical trials. Both the tools available to us, and our unique location at NewYork-Presbyterian/Weill Cornell Medical Center, allow us to move biological research forward while rapidly translating our findings to therapy.”
Written by Petra Rattue