Identifying Molecular Changes That Drive Cancer

From the time scientists began to identify cancer-causing genes, or oncogenes, in humans more than 30 years ago, they began to explore the possibility that targeting the proteins produced by these genes might kill cancer cells or slow their growth. NCI-supported basic and clinical research validated this approach, ultimately leading to Food and Drug Administration (FDA) approval of drugs such as trastuzumab (Herceptin®), imatinib mesylate (Gleevec®), and cetuximab (Erbitux®). NCI-supported research also led to FDA-approvals of drugs, such as bortezomib (Velcade®), everolimus (Afinitor®), and dinutuximab (Unituxin®), that target other molecules in cancer cells besides the proteins produced by oncogenes.

Currently, more than 35 molecularly targeted therapies have been approved by FDA for use by cancer patients. Despite this progress, more research is needed to understand the mechanisms that drive cancer. This research will help to identify additional molecular targets, to generate “lead compounds” that act against those targets, and to advance candidate drugs through the preclinical and clinical development processes.

In addition, more research is needed to understand the mechanisms by which cancer cells develop resistance to cancer therapies, including molecularly targeted therapies, and how to overcome this resistance. Drug resistance is one of the main causes of cancer treatment failure and reduced survival for patients.

Research Priorities

NCI is committed to increasing our fundamental knowledge of the inner workings of cancer cells to identify new molecular targets and to translate those discoveries into therapies that will improve the lives of cancer patients.

Discover New Molecular Targets

The genomics revolution and technological advances that followed the completion of the Human Genome Project have allowed researchers to molecularly characterize many human cancers. One important, recently completed initiative was The Cancer Genome Atlas (TCGA), in which the genomes of more than 30 types of cancer were characterized to identify genetic alterations in the cancer cells that might be targeted therapeutically. TCGA researchers identified thousands of genetic alterations, including many potential targets. FDA-approved drugs exist for some of these targets, and additional drugs that target other genetic alterations are in various stages of development.

NCI-funded scientists are working to fully understand the role of these genetic alterations in cancer development and progression, identify ways of targeting them, develop new molecularly targeted therapies, and, ultimately, test the therapies in clinical trials to determine whether they will benefit cancer patients.

Specific NCI-supported initiatives and programs in this area include:

  • The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, which focuses on identifying molecular targets in several aggressive hard-to-treat childhood cancers. TARGET investigators have made many novel discoveries, including the identification of a distinct molecular subtype of pediatric acute myeloid leukemia that may respond to treatment with drugs called JAK kinase inhibitors. (Learn more about how TARGET is helping to develop new treatments for children with cancer.)
  • The Cancer Target Discovery and Development Network (CTD2), in which researchers seek to functionally validate discoveries made in large-scale genomic studies that, upon further investigation, may lead to the development of new therapies. This validation may involve molecular and biological assays or computational analysis.
  • The Developmental Therapeutics Program (DTP), which provides services and resources to academic and private-sector researchers worldwide to facilitate the discovery and development of new cancer therapies. Since its inception by Congress in 1955, DTP has supported the development of more than 40 U.S.-licensed cancer drugs through extensive collaborations with academic institutions and pharmaceutical and biotechnology companies.
  • The NCI Experimental Therapeutics Program (NExT), a DTP effort that seeks to translate breakthrough discoveries in basic and clinical research into new cancer therapies while shortening the timeline for drug development. Both CTD2 and NExT are intended to complement the drug development efforts of pharmaceutical and biotechnology companies by supporting meritorious, high-risk research. Dabrafenib (Tafinlar®), trametinib (Mekinist®), and nivolumab (Opdivo®) are examples of FDA-approved drugs that were developed with the support of NExT.

Target Difficult-to-Drug Molecules

Although we have successfully developed therapies that target the proteins produced by many oncogenes, there is still much work to be done. For example, members of the MYC and RAS gene families are frequently altered in human cancer, but drugs that directly target their protein products have yet to be approved by FDA.

  • The RAS gene family includes the genes HRAS, KRAS, and NRAS. Mutations in these genes cause more than 30% of all human cancers, including 95% of pancreatic cancers and 45% of colorectal cancers. Cancers that have a RAS mutation generally have a poor prognosis. Developing drugs that effectively target mutant RAS proteins is a major research challenge. In one such effort, NCI-funded researcher Kevan Shokat, Ph.D., of the University of California, San Francisco, generated small molecules that target a specific alteration in KRAS. (Read about Kevan’s work.)

    In 2013, NCI launched the RAS Initiative to accelerate progress in this area. Under this initiative, researchers are exploring innovative approaches to target RAS-driven cancers, with the goal of finding effective therapies for patients with these cancers. Based at the Advanced Technology Research Facility of NCI’s Frederick National Laboratory for Cancer Research, the initiative brings together scientists from NCI’s intramural research program, academia, and biotechnology and pharmaceutical companies. The RAS Initiative highlights NCI’s ability to convene experts from across the research enterprise to address complex problems in cancer research.

  • The MYC family of genes, which was discovered decades ago and includes the MYC, MYCN, and MYCL genes, has been shown to be a critical player in the development of approximately 15% of human cancers and in drug resistance to targeted therapies. Despite this knowledge, no drug has been developed that targets MYC proteins directly. However, recent work by NCI-funded researchers and others has led to the discovery of a promising new class of dual-action inhibitors that block the activity of two other proteins, BRD4 and PI3K, that are necessary for the activation and stabilization of MYC proteins.

This work and other recent advances in the drug discovery field have renewed enthusiasm for our ability to hit targets that once were thought to be “undruggable.”

Stories of Impact

NCI supports research to identify the molecular drivers of cancer and to develop innovative therapies that target them. This research includes efforts to target important, known drivers of cancer for which no FDA-approved drugs exist.

Thinking Chemically to Discover New Targeted Cancer Drugs

Chemical biologist Kevan Shokat brings a unique perspective to the development of molecularly targeted therapies. He began his research career as an organic chemist, only later turning to biology. He believes that this hybrid training enables him to “think chemically” but with a deep enough understanding of biology to know what to focus on in addressing major biomedical challenges. Importantly, he believes we need to unwind many of our assumptions about things and conduct research in an open-minded, open-ended way. “That will lead us to fundamental discoveries,” he said, “and, every so often, you’ll overturn some dogma and that will be the crack in the problem.”

Encouraged by pioneers in the study of oncogenes—altered genes that have the potential to cause cancer—Kevan entered the field of cancer drug discovery. Among the oncogenes he sought to target were members of the RAS gene family, which play an important role in more than 30% of all human cancers, including 95% of pancreatic cancers, 45% of colorectal cancers, and 35% of lung cancers. The proteins produced by RAS oncogenes had long been thought to be “undruggable” because they lack a clear binding site for drug attachment. Kevan, however, prefers to view them as “not yet drugged.”

Key Takeaways

  • NCI supports research to understand the molecular basis of cancer and to identify molecules in cancer cells that are potential therapeutic targets.
  • NCI supports research to develop molecularly targeted therapies for cancer, including therapies that target yet-to-be-drugged molecules.