Learning From 'Smart' Drugs

Targeting Genes, Proteins, and Immune Cells

From Turning Point 2014

By Robert Levy

Success is a precious commodity in cancer research. When a study shows a new treatment to be effective, whether in the laboratory or in patients, scientists strive to learn everything they can from it – the insights it provides into the basic mechanics of cancer, and the benefits it may hold for patients with other forms of the disease.

Illustrating this trend are so-called smart drugs, which disable cancer cells by blocking the genes and proteins that make them proliferate. It was in breast cancer, in fact, that scientists first demonstrated that attacking vulnerable proteins on tumor cells could be an effective strategy for treating solid tumors. Over the past 15 years, smart drugs have gained a permanent place in the anti-cancer arsenal, as scientists have identified dozens of potential target genes and proteins and developed an expanding array of drugs capable of hitting those targets.

Today, researchers and physicians at the Susan F. Smith Center for Women's Cancers at Dana-Farber are pioneering work in laboratory discoveries, drug development, and clinical applications that have led to the advent of targeted therapies for breast and gynecologic cancers. Like the earlier drugs, these novel agents aim where cancer cells are most vulnerable: the genes and proteins that help them grow and survive. Many new studies involve combinations of targeted therapies and frontline chemotherapy agents. Other research focuses on the problem of drug resistance, in which cancer cells gain the ability to rebuff standard therapies.

The Heedless Cell

About 75 percent of breast cancers are ER-positive, meaning they grow in response to the hormone estrogen. While surgery and hormone-blocking drugs are often effective at treating these tumors, better therapies are needed, especially for cancers that spread beyond the breast.

One type of targeted therapy turns cancer cells' own recklessness against them. Normal cells divide in a deliberate, fastidious manner, with plenty of pauses along the way. At each pause, or "checkpoint," cells inspect for damage, much as a writer might stop every few sentences to do a spell-check. If something is amiss – an improperly duplicated chromosome, for example – the cell will initiate repairs, or, if the problem is too extensive, sacrifice itself for the good of the body.

Cancer cells know nothing of such caution, barging through checkpoints with a rashness that allows genetic damage to accumulate within the cells. The silver lining to this behavior is that it presents researchers with a choice target for smart drugs.

In many cancers, a protein called pRB, which normally keeps cell growth in check, is shut down by an increase in activity in the proteins CDK4 and CDK6. "That can cause the cells to divide over and over, rather than obeying the signals that instruct them to stop at key checkpoints," says Sara Tolaney, MD, MPH, of the Susan F. Smith Center.

Dr. Tolaney is leading a series of clinical trials of CDK4 and 6 inhibitors in women with estrogen driven breast cancer. Although many of these trials are in the early stages, when investigators are focusing on the drugs' safety and proper dosage, other trials are even more advanced and could soon lead to changes in clinical practice.

Sensitizing Cells

If a cancer cell isn't susceptible to a particular targeted therapy, can another drug make it become susceptible? That is the strategy behind a clinical trial testing a new treatment for triple-negative breast cancer, a disease named for its ability to grow without the hormones estrogen or progesterone, or the protein HER2.

The treatment involves drugs known as PARP inhibitors, which treat breast cancers with mutations in the genes BRCA1 or BRCA2. The defective genes create a weakness in tumor cells – a reduced ability to repair damaged DNA – which PARP inhibitors can exploit.

The majority of triple-negative breast cancers, however, do not possess BRCA1 or 2 mutations and may not be vulnerable to PARP inhibitors. But Geoffrey Shapiro, MD, PhD, director of Dana-Farber's Early Drug Development Center, discovered that blocking CDK1 (a protein cousin of CDK4 and 6) can disrupt BRCA, potentially making cells vulnerable to PARP inhibitors. With Dana-Farber's Alan D'Andrea, MD, Dr. Shapiro has extended those findings and has opened a phase 1 clinical trial of a CDK1-inhibiting drug and a PARP inhibitor in patients with a variety of cancers.

If the phase 1 trial shows the combination is safe, Erica Mayer, MD, MPH, of the Susan F. Smith Center, plans to launch a phase 2 trial to see if the regimen is effective in women with triple-negative breast cancer. "This work, funded by our SPORE [Specialized Program of Research Excellence] grant, shows what can be accomplished when we work together as laboratory and clinical researchers to help patients benefit from recent scientific advances," Dr. Mayer says.

Micromanaging a Treatment

In ovarian cancer research, Panos Konstantinopoulos, MD, PhD, of the Gynecologic Oncology Program, is working to overcome the problem of resistance to PARP inhibitors.

"We've discovered that many of these tumors upregulate [increase the activity of] molecules called microRNAs, which control the activity of other genes throughout the cell," Dr. Konstantinopoulos says. "One result is that the cells gain the ability to grow even when PARP inhibitors are present.

The microRNA finding is important for two reasons. First, it may help doctors identify patients who aren't likely to benefit from PARP inhibitors because of an upregulation of microRNAs. Second, it provides a potential target for drugs in tumors that no longer respond to PARP inhibitors. "We can potentially target microRNAs with special molecules called antagomirs," Dr. Konstantinopoulos says. "This raises the possibility that we can take away a crucial growth pathway in these tumors."

Releasing the Brakes

Smart drugs need not only target cancer cells. One promising approach to cancer therapy – dubbed the 2013 "Breakthrough of the Year" by Science magazine – takes aim at immune system cells known as T cells, a key part of the body's disease-fighting corps.

In the early 2000s, Dana-Farber scientists showed that cancer cells can dodge an attack by the immune system by tweaking a molecule called PD-1 on T cells. The molecule triggers a braking mechanism within T cells that prevents them from assaulting the cancer cells. Researchers showed that drug agents that target PD-1, or the corresponding molecule on cancer cells, can loosen those brakes, exposing cancer cells to the full force of the immune system.

In 2010, Dana-Farber's F. Stephen Hodi, MD, reported that the drug ipilimumab, an antibody that releases a separate braking system within T cells, extended the lives of patients with advanced metastatic melanoma, in some cases for many years.

Physician/scientists are studying immune system therapies for both breast and gynecologic cancers. Ursula Matulonis, MD, and medical director of the Gynecologic Oncology Program at the Susan F. Smith Center, and her colleague Joyce Liu, MD, MPH, are partnering with Dr. Hodi to test Ipilimumab in patients with ovarian cancer.

Turning Point 2014 Table of Contents