Patient with vaginal cancer with DDR mutation benefits from clinical trial

In March 2019, Shelly Busby began experiencing unusual vaginal bleeding. Frightened and concerned, she went to her OB/GYN for an examination and biopsy.

“There was something there that didn’t belong,” says Shelly, 67, a retired schoolteacher. “There was a tumor, and before I knew it, I was having surgery to have it removed.”

She was diagnosed with stage III vaginal cancer, for which there is currently no approved therapy. After undergoing chemotherapy and radiation therapy, Shelly thought she was cancer-free for about a month. Her scans and tests looked promising at first, but she wasn’t out of the woods: the cancer had begun to metastasize to her retroperitoneum and her abdominal lymph nodes.

Shelly booked a flight from her home in Colorado to Texas to meet with gynecologic oncologist Karen Lu, M.D., at MD Anderson, who wanted to start her on another chemotherapy regimen in hopes that it would keep the cancer at bay. However, the drug wasn’t covered by Medicare so they had to come up with a plan B.

“Dr. Lu said, ‘I have somebody I want you to meet.’ That person was Dr. Yap,” Shelly recalls.

Genomic sequencing targets the Achilles’ heel of cancer cells

Lu ordered a molecular test and liquid biopsy in March 2020 to check if Shelly had any genetic mutations that might be driving her cancer. The results revealed that she had a DNA damage response mutation, also called DDR.

Thanks to advanced genomic sequencing of cancer, researchers have been able to identify tumor-specific genetic alterations and biological changes that drive cancer growth. This allows them to recognize and exploit weak links in cancer DNA to target tumors selectively. Timothy Yap, M.D., associate professor of Investigational Cancer Therapeutics and medical director of MD Anderson’s Institute for Applied Cancer Science, is doing this is by targeting cancer cells’ ability to repair its DNA, a process called DNA damage response.

Because cancer cells replicate uncontrollably and more rapidly, their DNA is more prone to damage than normal cells. Like an addiction, cancers with certain mutations become heavily dependent on these repair pathways to activate the DDR mechanism. Without it, the cancer cells would fall apart and die.

PARP is one of the repair proteins that initiates the DNA damage response process. PARP inhibitors, such as olaparib and niraparib, are a class of DDR inhibitor drugs that have already been approved by the Food and Drug Administration to treat certain types of BRCA-mutated cancers, including advanced ovarian, breast, prostate and pancreatic cancers.

However, targeting BRCA mutated tumors with PARP inhibitors are just the tip of the iceberg, Yap says. Researchers are discovering new targets and developing potent and effective therapies against these key cancer vulnerabilities. The ATR repair protein is one of the other major DNA repair pathways that has emerged as a promising target to develop drugs against.

This is the Achilles’ heel Yap is targeting.

He and his team have identified 10 to 15 mutations so far that will potentially respond to ATR inhibitors irrespective of the tumor type, and with minimal effects on normal healthy cells.

“This is precision medicine at its finest. We are going beyond tumor types and are focused on targeting different mutations with potent and selective drugs,” Yap says. “For example, we don't want to treat breast cancer all the same way. What we're trying to do is to find out what that underlying mutation is through a tumor biopsy or a liquid biopsy blood test, then match them with rational treatments.”

Vaginal treatment success for Shelly

Yap’s team identified that Shelly had a DDR mutation. That made her an ideal candidate for his clinical trial. Yap started her on an ATR inhibitor combined with immunotherapy in October 2020.

By that point, Shelly had already completed standard of care chemotherapies and participated in two other clinical trials to no avail. But she was determined to try again. Her trust in her doctors and gratitude for her care team never wavered.

“Dr. Yap has made such a positive difference in my life,” Shelly says. “I am living my life and doing my part to stay healthy while Dr. Yap is treating me”

In January 2021, a CT scan showed a 76% reduction in Shelly’s cancer lesions from her previous scans before starting the ATR inhibitor clinical trial therapy.

When Yap called Shelly to tell her the good news, she cried tears of joy.

“She had never received any good news from any of the scans she’d had,” Yap says. “She always progressed, but this was the first treatment that shrunk her cancer.”

A recent restaging CT scan showed the Shelly continued to do extremely well, with an 83% reduction of her cancer legions on the ART inhibitor clinical trial treatment, which she continues to tolerate very well with no side effects.

Clinical trials explore a growing list of mutations to target

Yap currently leads multiple clinical trials of drugs targeting DDR mutations, such as BRCA1, BRCA2, PALB2, ATM, RAD51C and RAD51D mutations. He is continuing to gather more data, and his list of mutations that he predicts may be responsive to such ATR and other DNA damage response mechanism inhibitors continues to be refined.

As this area of precision medicine becomes increasingly personalized, Yap encourages patients to ask their physicians for molecular testing of their tumor biopsies, as well as liquid biopsy of blood for circulating tumor DNA sequencing. This can help determine if patients may be a match for an approved drug or clinical trial therapy.

“If they have any of these mutations on the list, we want to know so that we can provide them with a rational option that makes sense and increases the chance of treatment success,” Yap says.

Shelly, an eternal optimist, is grateful she decided to participate in Yap’s clinical trial and hopes more patients will consider enrolling in one.

“You'll never know unless you take a chance,” Shelly says.

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