A recent report by NPR science writer Richard Harris explores the efficacy of DNA sequencing in the treatment of cancer. Antonio Giordano, MD, PhD, President of the Sbarro Health Research Organization (SHRO) at Temple University comments on the potential, and the shortfalls, of this strategy in both the clinical and research setting.
“Only a few of the genetic mutations that occur in cancer actually act as ‘drivers’ to tumor malignancy,” Giordano says. “Most act simply as ‘passengers’ in the tumor.”
“This makes finding a genetic target for treatment like finding a needle in a haystack,” says Giordano.
With research focused on cell cycle mechanisms for over 30 years, Giordano’s work has often concentrated on the impact that genetic mutation has on natural cellular processes and the subsequent effect on the growth and spread of cancer.
“We have identified proteins which act as the engine of the cells, such as the cyclin-dependent kinases, as well as a key member of the retinoblastoma family of tumor suppressors which act as the ‘brakes’ on tumor growth,” says Giordano. “Based on this fundamental knowledge, with my collaborator Dr Francesca Pentimalli, we are currently developing strategies that can specifically target these mechanisms in cancer cells.”
“Many therapies are aimed at inhibiting active oncogenes, often identified through DNA sequencing,” Giordano says. “Alternatively, we are testing drugs designed to restore the body’s natural ability of the retinoblastoma protein RBL2/p130 to suppress cancer.”
“We predict this will be successful in treating cancer types in which the RBL2/p130 ability to inhibit tumor growth is suppressed by other oncogenic pathways, rather than mutated itself,” says Giordano.
The major difficulty in using DNA sequencing to identify a treatment target, Dr. Giordano says, lies in the heterogeneic nature of tumors.
“No tumor is identical to another from the molecular point of view, and, even a tumor from a single individual changes over time. Subpopulations and mutations occur as the tumor develops, through progression, and after it is challenged therapeutically,” Giordano says.
“This often renders DNA sequencing insufficient on its own to capture the complexity of tumour cells’ genetic machinery. Eventually the tumour microenvironment affects the stability and function of the protein coded by DNA and can ‘muddy the water’ when it comes to identifying a single genetic treatment target,” says Giordano.
“Fortunately, many alterations in cancer affect a limited number of cancer signalling pathways, and we already have therapeutic tools for many of these targeted genes in our anticancer drug arsenal,” Giordano says.
Lastly, Giordano believes more emphasis should be placed on effective communication of scientific breakthroughs to doctors and patients.
“Cancer DNA sequencing, and even other types of profiling, can be very informative,” says Giordano, “but the main hurdle is the cost-effectiveness of these approaches which cannot be routinely used in the clinical practice.”
“For example, late mutation can occur during the natural progress of tumor growth, and these sometimes act as a marker of resistance to treatment,” says Giordano. ”Similar to the story on NPR about Ben Stern, a patient in which a previously treated tumor had grown back, doctors and patients should consider the timing and signs of when DNA sequencing may offer a solution.”
“But sensational announcements should be avoided,” cautions Giordano, “and clinicians should avoid looking to DNA sequencing as a ‘magic bullet.’”
“The winning recipe must be to build on step-by-step achievements of research aimed at the same target: to improve the survival of patients with cancer,” Giordano concludes.