- Current drugs target mutations in cancer cells, but encounter resistance.
- New classes of potential drug targets are being identified.
- A report authored by William Hahn, MD, PhD, Dana-Farber executive vice president and chief operating officer, and others calls for a broader attack on emerging drug targets in tumors.
Cancer drugs like Gleevec or Herceptin, which were approved for us in the 1990s, prompted hopes of transforming cancer care and perhaps render harsh treatments like chemotherapy obsolete. Known as precision or targeted therapies, these drugs are designed to block the action of specific mutated genes or proteins that drive malignant tumor growth, while sparing normal tissues that lack such mutations.
Despite some notable successes, however, targeted therapies, have thus far fallen short of the grander hopes. Many drugs aimed at mutated cancer genes, known as oncogenes, don’t work as expected, or are initially effective, but falter as drug-resistant cancer cells rapidly emerge and the patients relapse.
Nevertheless, a new report published in CELL says that targeted therapy may yet have a bright future.
New types of potential drug targets identified
The optimism is based on discoveries of new types of cancer targets that have not been attacked with drugs. The report by the Cancer Target Discovery and Development Network (CTD2) says research has “identified new categories of cancer targets beyond those inhibited by approved cancer drugs. Indeed, the number and diversity of these putative cancer targets far exceed oncogenes identified to date.”
The first author of the report is William Hahn, MD, PhD, Dana-Farber executive vice president and chief operating officer. He is the Dana-Farber lead investigator for the CDT2 network, a collaboration involving researchers at a dozen institutions working to identify and validate multiple targets in cancer cells with the goal of overcoming resistance to treatment.
In their report, “An Expanded Universe of Cancer Targets,” the authors note that despite great progress in analyzing the genomes (all the genes) of cancer cells to find mutated or altered genes, the function of most cancer genes “remains mysterious.” As a result, “tumor genomic characterization does not influence therapy for most patients.”
However, says Hahn, it’s now believed that mutated genes — while important drivers of many cancers — account for only 10 to 20 percent of potential targets in tumors. “So that means there are a lot of targets out there.”
Targeted therapy had early successes with drugs like Gleevec, which transformed the treatment of chronic myeloid leukemia, and drugs that blocked the epidermal growth factor receptor (EGFR) in lung cancer. But it soon became apparent that most cancers, particularly solid tumors, owed their malignant behavior to many more complex factors than simply one mutated gene. For example, tumors may be driven by excess copies of a gene, rearrangements of segments of DNA on a chromosome, the loss of a tumor-suppressor gene, changes in molecular mechanisms that regulate gene expression, unrepaired DNA damage, and other defects.
New targets located both inside and around tumor cells
Some of these complexities, however, also offer insights into vulnerabilities in cancers that potentially can be exploited as drug targets, say the authors. The report lists several types of targets that are being studied and divides them into two categories. One is “tumor intrinsic” targets, meaning vulnerabilities in the cancer cells; the other is “tumor extrinsic,” referring to the microenvironment — a milieu of cells and proteins surrounding tumor cells and helping to regulate their biology.
One approach in tumor intrinsic targeting is known as synthetic lethality, used when the principal mutated protein driving the cancer is difficult to block with drugs. Instead, scientists can identify other proteins or pathways the mutated cancer cells need to survive and target them instead. An example is PARP inhibitors, which target molecules needed for survival by tumors driven by BRCA1 and BRCA2 mutations.
Strategies to treat cancer by attacking the microenvironment of tumor cells include anti-angiogenic drugs that disrupt the tumors’ blood supply. In addition, immune therapies, using modified immune system cells, continue to be a major area of drug development and investigation.
The authors say that developing new therapies that exploit the growing number of types of cancer targets described in the report “may provide the means to use targeted approaches for more patients” and “provides hope that all patients will benefit in the future from precision-medicine guided therapies.”