A Tale of Two Proteins

Discovering New Ways to Treat Cancers Driven by Proteins HER2 and HER3

From Turning Point 2014

By Robert Levy

Poking from the surface of many breast cancer cells, the protein HER2 makes a tantalizing target for drug therapy. In the first place, it's abundant: A breast cancer cell may be covered with up to 2 million copies of it, compared to 20,000 on a normal breast cell. Such profusion means that drugs targeting HER2 swarm around tumor cells while leaving normal cells unscathed.

Secondly, HER2 is no mere ornament on a breast cancer cell, but a vital part of its machinery for growing and dividing. As a result, drugs that interfere with HER2 can deal cancer cells a mortal blow.

In 1998, the U.S. Food and Drug Administration approved the drug trastuzumab (brand name Herceptin) – an antibody that specifically targets HER2 – for women with breast cancer whose tumor cells overproduce HER2. Such "HER2-positive" tumors tend to be particularly aggressive and account for about 20 percent of all breast cancers, or approximately 46,000 new cases annually in the U.S.

Trastuzumab and other targeted therapies are used – often in combination with standard chemotherapy – to treat women at various stages of HER2-positive breast cancer: from tumors confined to one section of the breast, to those that have spread to other parts of the body. For many of these patients, trastuzumab and similar agents have dramatically reduced the risk that the cancer will recur.

But trastuzumab isn't the end of the HER2 story. At the Susan F. Smith Center for Women's Cancers at Dana-Farber, investigators are working to better match therapies to the size and aggressiveness of HER2-positive breast tumors. They're studying treatments that attack such tumors with a two-in-one compound of antibody and chemotherapy. And they're probing HER3, a cousin of HER2 that holds promise as a target for ovarian cancer drugs.

Together, this work is making the treatment of HER2-positive breast cancers – and potentially some ovarian cancers – not only more effective but also longer-lasting and less prone to side effects.

Trying a Milder Approach

Thousands of women with HER2-positive breast cancer have participated in clinical trials showing that chemotherapy and a targeted therapy such as trastuzumab can reduce the chances that the cancer will recur. Most of those patients had large tumors (more than 2 cm in diameter) that had spread to nearby lymph nodes, raising the question of whether women with smaller, less-advanced tumors could fare just as well with a milder form of therapy.

Investigators at the Susan F. Smith Center have shown the answer to be a clear "yes." In place of standard therapy – which can include the chemotherapy drugs adriamycin, taxotere, and carboplatin – patients in a clinical trial received a less-harsh combination of the chemotherapy agent paclitaxel and trastuzumab for 12 weeks, followed by nine months of trastuzumab alone. All the participants had HER2-positive tumors smaller than 3 cm that showed no sign of spread to the lymph nodes.

After a median follow-up of 3.6 years, less than 1 percent of the study participants experienced a recurrence of their cancer in another part of the body, and less than 2 percent developed any type of recurrence.

"Until now, there hasn't been a standard approach to preventing cancer recurrence in this group of women," says Sara Tolaney, MD, MPH, who led the study with colleague Eric Winer, MD, director of the Susan F. Smith Center's Breast Oncology Program. "Our findings suggest that the gentler regimen represents a reasonable option for many of these patients."

A Potent Drug Combination

Like a savvy investor or a baseball scout, leaders of cancer drug clinical trials need to be adept at spotting potential – the novel agent or compound that has the best chance of success in patients. Dr. Winer and Ian Krop, MD, PhD, proved to be especially prescient in making the Susan F. Smith Center a major site for testing a new breast cancer agent known as T-DM1.

T-DM1 is a cancer cell's unwelcome guest. Consisting of an antibody attached to a potent chemotherapy agent, the compound latches onto cancer cells and is drawn inside them. Powerful enzymes then cut the tether, allowing the chemotherapy drug to destroy the cell from within.

Known as an antibody-drug conjugate (or ADC), T-DM1 takes advantage of antibodies' unique ability to hone in on cancer cells by recognizing proteins called antigens from the target cells' surface. From there, it summons an immune system attack on the cancer cells while also disrupting the internal signaling system that cancer cells need to survive.

Despite their tumor-targeting prowess, antibodies are often incapable of actually curing cancer on their own, which is why they're typically used in conjunction with chemotherapy. In the 1990s, researchers led by Dana-Farber's Lee Nadler, MD, pioneered efforts to fuse an antibody to a chemotherapy agent. Though that conjugate didn't lead to an approved drug, it did lay the conceptual foundation for today's ADCs.

In 2006, Dr. Krop began a clinical trial of T-DM1 – which couples trastuzumab with a potent cell toxin – in women with advanced HER2-positive breast cancer. The trial was so successful that Drs. Krop and Winer soon began campaigning for trials for patients with earlier stage disease. Two such trials are now underway: one for patients with high-risk cancers that combines T-DM1 with standard therapy, and one for patients with lower risk disease that uses T-DM1 instead of chemotherapy.

"T-DM1 has the qualities we're looking for in cancer drugs: it's highly effective and is delivered selectively to cancer cells," says Dr. Winer. "We're hoping it will be one of many conjugates that are effective against various forms of cancer."

A Sister Protein in Ovarian Cancer

Another member of the HER family – HER3 – is often found on http://www.dana-farber.org/Adult-Care/Treatment-and-Support/Ovarian-Cancer.aspx ovarian cancer cells. But it is not an equal-opportunity promoter of cell growth. As Joyce Liu, MD, MPH, and her colleagues in the laboratory of David Livingston, MD, have shown, certain ovarian cancer cells depend on HER3 in a way that normal cells do not.

"The way cancer cells rely on HER3 suggests that a drug targeting this protein might be lethal to certain ovarian cancer cells without harming normal cells," says Dr. Liu, of the Susan F. Smith Center's Gynecologic Oncology Program. "Our lab work showed that, in a subset of ovarian cancer cells, blocking the activity of HER3 can significantly affect the ability of ovarian cancer cells to survive and proliferate."

Teaming up with a pharmaceutical company, Dr. Liu conducted a phase 1 clinical trial of a HER3-blocking agent known as MM-121 in conjunction with the chemotherapy drug taxol in women with ovarian and breast cancer. More recently, she opened a phase 2 trial comparing taxol-only therapy to a combination of taxol and MM-121 in patients whose ovarian cancer doesn't respond to platinum-based chemotherapy drugs.

While the trials will provide a first indication of whether HER3-blockers can be effective in treating ovarian cancer, investigators also hope to discover biomarkers – telltale signals in the blood or tumor cells – that can reveal which patients are most likely to benefit from the taxol/MM-121 combination.

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