Dream Team Evaluates Direct Testing of Tumors

Alan D’Andrea, M.D., co-leader of the Stand Up to Cancer Dream Team on Ovarian Cancer, wants to know why diagnosing ovarian cancer can’t be more like diagnosing a sore throat.

Presenting an update on the Dream Team’s work during the 2018 Ovarian Cancer National Conference, sponsored by the Ovarian Cancer Research Fund Alliance, he said that when a person gets a sore throat, he or she goes to the doctor’s office and gets a throat swab. That swab gets cultured in the lab and, a few days later, the doctor’s office calls with a diagnosis and a treatment recommendation.

“The question has always been: In cancer, why can't we do that with tumors? Why can't we take a swab or a biopsy of a solid tumor, plate it out in a dish, grow it out for two or three or four days, and then test our drugs on these growing tumor cells?” D’Andrea, director of the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute in Boston, said during his July 14 talk in Washington, D.C. “Is it sensitive to a PARP (protein) inhibitor? Is it sensitive to a carboplatin (chemotherapy)? Is it sensitive to an immunotherapy? Is it sensitive to a combination of those drugs? Why can't we do testing directly on the tumors themselves?"

The breakthrough, he said, is that investigators are learning how to take a tumor biopsy from a newly diagnosed or relapsed patient, chop it up into a single-cell suspension and grow small tumors called organoids within a week. D’Andrea believes that direct testing on these organoids will help physicians find the best combination of drugs to kill tumor cells "right now." For a short time, these organoids look and behave exactly like the larger tumor.

"Now, you can do a direct drug testing on these organoids just like you do with a throat culture for penicillin testing,” he said. “You can test these little organoids for their sensitivity to a drug.”

Chemotherapy sensitivity testing on cell lines has existed for a couple of decades, but testing on organoids is a newer method with the potential for higher accuracy.

Investigators collected tumor cells from biopsies of 12 consecutive patients treated for ovarian cancer at Dana-Farber and grew organoids of their cancers. Three women’s cancers expressed BRCA gene mutations and one expressed a RAD51C mutation, making this group a reasonably good representation of ovarian tumors in the general population, according to D'Andrea.

He highlighted results from the analysis of one patient's organoids. She was found to have the BRCA1 gene mutation, suggesting that her cancer should respond well to a PARP inhibitor such as Lyparza (olaparib), but her organoids showed that her cancer was resistant to the drug.

“This woman's ovarian tumor . . . in the clinic was not responding to the PARP inhibitor,” D’Andrea said. “Her clinical response, in the clinic, was matching the sensitivity and resistance of these organoid cultures in the laboratory.

“This is the kind of information we can give to the clinician — quickly. We can say, 'You know, these organoids are very resistant to the PARP inhibitor; maybe we should switch to a different drug, and do it early.'

“We can't say that yet, because this hasn't been clinically certified the way that penicillin testing for a sore throat is. But we're getting there.”

D’Andrea said this method of direct testing will be particularly effective and important for predicting drug resistance. He highlighted another patient, the one whose tumor expressed the RAD51C mutation, noting that her organoids were resistant to every drug investigators tried. In line with that finding, her disease was not responding to treatment in the clinic.

“There really did seem to be a perfect match between the resistance of the drugs in the test tube and the resistance of the tumor in the patient,” he said. “We found this out within two weeks of the time of the biopsy. So, rather than put this patient through four cycles of chemotherapy that's not going to work, why don't we get that information back to the doctor sooner so we can switch to a combination of drugs, or maybe try a clinical trial of a new immunotherapy agent?”

D’Andrea noted that direct testing is in the earliest stages of evaluation. Nonetheless, he has high hopes for the future of direct testing.

“It’s a kind of precision medicine, and I think over time, this is going to grow in utility,” he said.

Stand Up To Cancer, a division of the nonprofit Entertainment Industry Foundation, raises money for grants it gives to 22 Dream Teams of scientists from various hospitals and institutions who collaborate to develop new treatments. SU2C is 10 years old, and in that time, it has accepted more than $480 million in pledges to support its cancer research, and the work of its scientists has contributed to the Food and Drug Administration’s approval of five new cancer treatments.