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Ex Vivo Drug Resistance, Sensitivity Screening Explored for Treating Metastatic Melanoma


NEW YORK – Researchers from the University of Helsinki have demonstrated the feasibility of an ex vivo drug screening approach for personalizing treatment options for metastatic melanoma patients, which they hope to test in a clinical trial.

The pilot study, published in Translational Oncology last month, established an ex vivo drug sensitivity and resistance testing, or DSRT, protocol using patients' own cancer cells. The researchers are now exploring how well the DSRT approach predicts patients' responses to drugs in a larger optimization study.

"We wanted to see how much information we will get from doing ex vivo drug testing with patient-derived cancer cells," Laura Kohtamäki, the study's first author, wrote in an email.

The DSRT protocol, and ex vivo screening in general, is attractive, Kohtamäki noted, because it allows simultaneous testing of a variety of drugs and drug combinations. In comparison to conventional molecular or murine drug screening, "we think that this approach opens more specific options for the patient," she said.

In their recent study, the researchers recruited six patients with unresectable metastatic melanoma who had failed standard therapy. Tissue samples were taken from either subcutaneous or lymph node metastases in each participant, but due to poor viability of the melanoma cells and overgrowth by fibroblasts, stable patient-derived cell lines, or PDCs, were only successfully generated from three patients, each with BRAF wild-type and NRAS-positive tumors.

The team subjected the three PDCs, as well as five established melanoma cell lines for comparison, to drug sensitivity and resistance testing using 527 investigational and clinically approved oncology compounds from a small molecule library maintained at the Finland Institute for Molecular Medicine, or FIMM.

Consistent with pathways known to be affected by NRAS mutations, Kohtamäki and her colleagues saw that the PDCs were sensitive to inhibitors for PI3K, mTOR, PLK1, MEK, ERK, and RAF. Some PDCs had particularly robust responses to the MEK inhibitors trametinib (Novartis' Tafinlar), cobimetinib (Genentech's Cotellic), and binimetinib (Pfizer's Mektovi).

Individual PDCs also showed different sensitivities to specific drugs, indicating the potential for individualized treatments based on ex vivo findings.

The team also tested cellular resistance and sensitivity to combination therapy, as monotherapy regimens often spur resistance. As cobimetinib showed the greatest efficacy overall in the PDCs, the researchers paired it with ten other drugs at seven concentrations. They observed that cobimetinib had synergistic effects when combined with ponatinib (Takeda's Iclusig), nilotinib (Novartis' Tasigna), the HSP90 inhibitor ganetespib (that was at one time being developed by Syntax Pharmaceuticals), and Selleck Chemicals' PI3Kα/δ inhibitor pictilisib.

This pilot study builds upon past research conducted at FIMM, which has been investing in ex vivo drug matching research.

One study preceding Kohtamäki's, for example, identified targeted therapies for 97 percent of 186 AML patients based on ex vivo DSRT. That study reported a 59 percent objective response rate for the individually tailored therapies, including 13 complete responses, and bridged five AML patients to allogeneic hematopoietic stem cell transplantation.

While the pilot demonstrated the feasibility of "matching" patients to drugs based on the DSRT approach, the drugs identified in this study were not given to study participants, as the three whose biopsies became viable PDCs were in remission and did not need further treatment. As such, based on the pilot study results one cannot conclude whether the matched therapies would benefit patients.

However, Kohtamäki and her colleagues are now planning a larger clinical trial to look at how DSRT-matched drugs impact patient outcomes. For this study, the researchers have recruited five melanoma patients out of a target 15 participants. "The aim in the expanded study is to optimize the process from biopsy to DSRT results," Kohtamäki explained, "as well as [to] test treatments for study patients in need of treatment without standard options left."

Researchers will track how many DSRT matches are made in the study as well as patients' response rates and adverse events on the recommended treatments.

As Kohtamäki's group refines its DSRT platform, a number of companies have launched ex vivo screening platforms in the marketplace in the hopes of demonstrating that this approach yields results faster and with less cost than genomic testing-based treatment personalization. In October, Crown Bioscience launched its 3D Ex Vivo Patient Tissue Platform, designed to measure oncology and immuno-oncology drug-induced tumor killing, along with endogenous immune cell proliferation.

Notable Labs recently announced a partnership with biotech CicloMed, in which it will use its predictive precision medicine platform to predict which patients respond to CicloMed's investigational acute myelogenous leukemia drug fosciclopirox. Notable's platform involves exposing patients' cancer cells to the treatment ex vivo, analyzing dynamic signals reflecting responses, and translating these findings into predictive algorithms using machine learning.

A recent study conducted by an Austrian group also recently showed that this sort of ex vivo approach to precision medicine improved survival among leukemia and lymphoma patients.

Kohtamäki and colleagues are working to add their approach to this growing list of ex vivo screening platforms and are focused on advancing their expanded melanoma trial. Before they can start the trial, however, they must establish the slate of drugs they'll test on PDCs. Based on the results of the pilot study, the researchers will leave chemotherapy drugs out of the panel, as melanoma patients tend to be chemotherapy resistant, but will include inhibitors of BRAF, MEK, ERK, and pan-RAF, as well as multi-kinase inhibitors.

The screening panel may include other drugs. "We have not decided yet the final setup," Kohtamäki said.

The researchers are hopeful that their study will offer another avenue for personalizing treatments for a group of cancer patients with an unmet need. "For patients with BRAF wild-type [metastatic melanoma] whose first-line immunotherapy was unsuccessful, the need for further effective treatment options is imminent," Kohtamäki and her collaborators wrote in their Translational Oncology paper. "According to our preliminary results, ex vivo drug testing with PDCs may provide a step closer in the process for identification of personalized treatment options for these patients."