In the biography of cancer, retinoblastoma (RB) is a lead character. First implicated in the cancer of the retina that bears its name, RB is a protein that is critical in regulating the life cycle of cells. Researchers have found that this protein is important in the life cycle of many types of cells, not only those in the eye. RB is a “tumor suppressor” protein, meaning that if it is inactivated, the “tumor” is no longer “suppressed” and is free to grow aggressively.
The pathway that RB is involved in is altered in 70 percent of human cancers—especially cancers in the brain. The RB pathway is abnormal in nearly 80 percent of patients with Glioblastoma multiforme (GBM), the most common malignant brain tumor. GBM is a devastating diagnosis for a neurosurgeon to deliver to a patient and their family, one with a dismal outcome. (GBM is what killed the late Senator Ted Kennedy.)
The current standard of care is to surgically remove as much of the tumor as possible, and then further treat with radiation and chemotherapy. Even with this multidimensional approach, patients survive for little more than 14 months from the time of diagnosis, a number that hasn’t changed in 20 years. New treatments are on their way, but have yet to be proven. New drugs that target GBM’s ability to commandeer life-giving blood vessels from non-cancerous tissue and therapies that work to stimulate the body’s own immune system to battle the tumor are just a few of the many possibilities being investigated.
But a new finding from Washington University in St. Louis demonstrates that there are fundamental cancer principles that we still do not understand. It is well-established that GBM is more common in men; in fact, males have a lower five-year survival rate when compared to females with GBM and other malignant CNS tumors. Until now, a biological understanding of this difference did not exist.
Dr. Joshua Rubin and his team discovered that RB is significantly less active in male brain cells. Properly functioning, fully active RB can be thought of as having anti-tumor effects. It seems that males have a less robust RB-based anti-tumor arsenal. Observing a sex difference in a patient population is important, but finding a cellular parallel is truly remarkable.
Rubin studied RB and two other genes implicated in cancer, neurofibromin and p53. Of the three, RB was more likely to be inactivae in male brain cells. To make this finding even more compelling, Rubin de-activated RB in female brain cells. Once RB was turned off, female cells were equally susceptible to becoming cancerous.
It is wholly possible that a drug’s effects are being understated because males and females respond differently to it.
Sex-specific differences in human diseases, like cancer, are a well-described phenomenon often attributed to the difference in powerful sex hormones, like estrogen, at different time periods of life. That was a clue for Rubin. Sex differences in brain cancer cannot be explained by age-related hormonal changes. The risk of developing a brain tumor as a male is higher than for females, independent of changes in hormone productions and levels.
This finding not only has significant implications for the treatment and management of GBM, but also for the field of cancer research. There are currently drugs that target RB in clinical trials, where researchers are testing if a drug that triggers RB’s anti-tumor potential can extend survival. But results from clinical trials do not necessarily take into account a biological difference between the treatment of response for males and females. Perhaps that should change. It is wholly possible that a drug’s effects are being understated because males and females respond differently to it.
The new finding also calls into question a catch phrase of translational research: taking research from the “bench to the bedside.” This mantra supports taking findings from a laboratory “bench” and translating them into clinically meaningful tools and therapies to use at a patient’s “bedside.” In identifying a cellular parallel to a well-established clinical observation (that GBM is more common in males), Dr. Rubin highlighted the need for further inquiry into sex differences in diseases, treatments, and clinical trials. There are multiple clinical aspects of GBM, and other cancers, that are not understood at a biological level. This is in spite of monumental findings in basic cancer research. Perhaps by emphasizing the need for explaining these phenomena—going from the bedside to the bench—we can begin developing more focused treatments for elusive and devastating illnesses like GBM.