Issue 7 – June 2012

Cancer Genomics Educational Series

Targeted Cancer Therapies: Molecular Insight Driving a New Generation of Drugs
Shannon Behrman, Ph.D.

In the context of finding new and improved cancer treatments, cancer genomics researchers often talk about identifying “molecular targets” and developing “targeted therapies”, but what exactly do these terms mean? In this article, we explore these concepts and reveal how they are transforming the way we treat cancer. This article is the first installment of a series of educational pieces that will explore various aspects of cancer genomics research.

In the 1940s and 1950s, patients had little chance of surviving cancer even with early advancements in surgical and radiation therapies. Frustrated with continually fighting a losing battle, physicians decided to take an entirely different approach to treatment: chemotherapy. They knew very little about the disease and its origins, except that cancer cells divide faster than their normal counterparts. Armed with this observation, physicians tested the efficacy of a variety of toxic compounds (ones that generally target rapidly dividing cells) in treating different types of cancers in human patients. This empirical approach to medicine ultimately proved quite successful and, consequently, many of these compounds were approved for clinical use. Today, these drugs or their derivatives remain part of the standard chemotherapy regimen used to treat most cancers.

Chemotherapies have dramatically reduced cancer deaths over the last 50 years. However, the need for novel, more effective drug therapies is imminent. Chemotherapies are poisons by nature and work by indiscriminately killing all rapidly dividing cells, including both cancer and normal cells. Consequently, they are very harmful to the human body and can produce lasting adverse side effects. Furthermore, many of the improvements to the survival rates of certain cancers are starting to plateau. In 1975, acute lymphoblastic leukemia (ALL) patients under the age of 65 had a 43% 5-year survival rate. Now, the 5-year survival rate is ~70%, where it has hovered since 1996. More than 1 out of every 4 ALL patients die within 5 years of their initial diagnosis, and current therapies have not shown significant progress in recent years. As Dr. Peter Adamson, Chair of the Children’s Oncology Group, stated in this issue’s interview, “We’ve learned how to use these chemotherapies better over time, but I think we’ve gotten as much mileage as we can from them.”

As our knowledge of the underlying biology of cancer expands, investigators are discovering novel ways to specifically target cancer cells with minimal damage to healthy tissue. Research since the 1960s has generated enormous insight into the genetic origin and molecular biology of cancer. Thanks to seminal work from Drs. Michael Bishop, Harold Varmus, and others, we know that cancer is caused by changes in our own genes. Genes produce molecules that participate in a wide array of cellular processes that are tightly controlled in normal cells, such as cell growth and survival. In cancer cells, however, changes (e.g. mutations) in genes that play a key role in cell growth and survival disrupt the normal function and regulation of these processes. The result is the uncontrolled growth of cancer cells at the expense of normal cells. By targeting the rogue molecules born from these genetic changes, investigators ascertained they could interfere with their tumor-promoting activity and effectively stop tumor growth. Drugs that are designed to selectively bind to these vulnerable “molecular targets” and stop their cancer-causing activity are called “targeted therapies.” Because targeted therapies preferentially block the growth of cancer cells over normal cells, they are more effective and less toxic than standard chemotherapies.

Most targeted therapies come in one of two forms: monoclonal antibodies or small-molecule inhibitors. Unable to cross the cell membrane barrier, monoclonal antibodies bind molecular targets outside the cancer cell (e.g. growth factors) or on the cell surface (e.g. growth factor receptors). They block their target’s activity by providing a physical obstruction, delivering a toxin or radioactive molecular “bomb,” or flagging the attention of the immune system. More diminutive in size, small-molecule inhibitors can pass through cell membranes and target molecules inside the cancer cell as well as on the cell surface. They wedge themselves into the structures of their targets, such as enzymes, ultimately inhibiting its activity.

Identifying a “good” molecular target is crucial in developing a successful targeted therapy. Rather than using a classical genetics approach to look for candidate targets one gene at a time, investigators are employing modern genomics methods (as well as other “-omics”) to view hundreds or thousands of genes all at once. Thus, modern genomics is akin to the invention of electricity. Instead of using a gas lamp to find a set of lost keys in a house, you are now able to illuminate most of the house by turning on the overhead lights. An example of a common high-throughput genomics approach is DNA sequencing. Investigators use sequencing to read the complete genetic code, or genome, of tumors. Applying careful computational analyses, investigators compare the genomes of tumors to those of normal tissue in order to identify mutations that are unique to the tumors studied. Because not all mutations have functional consequences, investigators separate the wheat from the chaff through a series of experiments that help reveal whether the mutations contribute to the initiation, progression and/or metastasis of tumors. If a molecular change resulting from a mutation demonstrates functional ties to tumor biology, then it may prove useful in detecting and treating the disease. In other words, it may constitute a “good” target. One classic example of a good molecular target is the BCR-ABL1 kinase, which is present in most cases of chronic myelogenous leukemia (CML). BCR-ABL1 is a fusion gene that results when two segments of separate chromosomes (chromosomes 9 and 22) abnormally trade places. The resulting BCR-ABL1 molecule perpetually activates the proliferation of white blood cells, leading to the formation of CML. Researchers developed a kinase inhibitor, imatinib (Gleevec), which targets the BCR-ABL1 kinase and stops the proliferation of these cancerous cells. The success of imatinib in treating CML patients paved the way for the development of other similar targeted therapies.

As we continue to uncover the immense genetic complexity and heterogeneity of tumors, it is clear there will be no “magic bullet.” However, using the genetic makeup of hard-to-treat tumors to design targeted therapies signifies progress in the area of cancer research and exemplifies the newly-emerging form of medicine called “precision medicine.” For instance, research demonstrates that a breast cancer patient may have one of many tumor subtypes, each defined by the presence or absence of certain molecular features, such as high levels of the estrogen receptor or the human epidermal growth factor 2 (HER-2). The overabundance of HER-2 promotes the rapid growth of breast cancer cells, and so HER-2-positive patients historically have very poor prognoses even after standard chemotherapy treatment. Fortunately, targeting HER-2 with trastuzumab (Herceptin) has shown tremendous success in treating this disease since its FDA-approval in 1998. Identifying which subtype a breast cancer patient has is, thus, essential in providing the correct therapy.

Rather than relying on the traditional trial-and-error approach to cancer drug development, investigators are using insights into the molecular underpinnings of cancers to develop a new generation of more effective, less toxic drugs. Some FDA-approved targeted therapies, such as imatinib and trastuzumab, have already revolutionized treatment of certain cancers. With many in the clinical trial pipeline, the pool of targeted therapies approved by the FDA is growing. All in all, targeted therapies show great promise in increasing the chance of survival and improving the quality of life for many cancer patients – especially for those where current chemotherapies are inadequate at treating their disease.