New approach finds drug combinations to stop cancer

In the future, the most effective cancer drug therapies will likely be combinations that not only target cancer cells but also drive cancer-suppressing responses in non-cancer cells in and around tumors. Identifying such drug combinations remains a challenge.

In a new study, researchers quickly identified effective treatment combinations against a mouse model of breast cancer using an implanted microdevice to track tumors’ varying responses to a multitude of different drugs at the same time.

“Although intended as a proof of concept that analyses of local nanodose drug responses can effectively guide systemic treatment strategies, we have already identified specific therapeutic combinations that warrant clinical consideration,” the researchers report in Nature Biotechnology. Joe W. Gray, Ph.D., professor emeritus of biomedical engineering in the OHSU School of Medicine, is a senior author, along with Oliver Jonas, Ph.D., an assistant professor of radiology at Harvard Medical School.

The microdevice looks like a pin with 18 holes along its sides. The holes are wells to load with a drug or combination of drugs that seep out from the implanted device into separate regions of the tumor. After a treatment period of a few days, researchers remove the tumor to measure the levels of dozens of different protein markers; define the types of tumor and microenvironments cells that are present; and identify shifting functional states of cells in each separate region of the tumor microenvironment. The researchers call the approach Multiplex Implantable Microdevice Assay, or MIMA.

The researchers predict that it will be feasible to use MIMA in patients to identify treatment combinations tailored for the individual.

The implantable microdevice is already being tested in human clinical studies across different cancer types. Data interpretation can be completed in less than 10 days, the researchers said — fast enough to support clinical decision-making.

“Should these studies show that MIMA results can be used to predict optimal drug combinations in humans, it opens the way to devise more effective treatment strategies that are tailored for the individual patient and that can be designed sufficiently rapidly to be deployed for the individual,” Gray said.

Release of the drugs from the device can be controlled to produce dose levels at each site in the tumor that are comparable to those achieved if the drug were given systemically, such as by intravenous infusion. Because the doses of drugs are minute, they do not generate the whole-body toxicities typically associated with systemic cancer treatments.

In the mouse experiments, the researchers used MIMA to evaluate the effects of five targeted anti-cancer agents (olaparib, palbociclib, venetoclax, panobinostat and lenvatinib) and two chemotherapies (doxorubicin and paclitaxel) to predict synergistic anti-tumor effects.

After treatment for three days, they removed tumors with the device in place, preserved them, and cut them into thin sections for imaging studies using tags to locate and identify more than 30 proteins. Computational analyses of the imaging makes it possible to characterize tumor cell states and classify all of the different cell types within the tumor microenvironment, including immune cells, vasculature and other non-cancer cells. This opens a window on drug-mediated mechanisms of response and resistance in each drug-delivery area.

The data predicted that palbociclib would synergize with anti-CSF1R, venetoclax with anti-CD40 and panobinostat with anti-PD-1 immunotherapy. The researchers validated these predictions using traditional systemic dosing studies. The triple combination of panobinostat, venetoclax and anti-CD40 triple therapy was the most effective in inducing complete tumor remission across multiple models of breast cancer.

The study revealed how drugs developed to target tumor cells also strongly affect the composition and organization of the tumor microenvironment in ways that influence overall tumor response. The successful drug combinations increased the association of cancer stem cells with dendritic cells during immunogenic cell death, which suggesting this spatial reorganization is an important mechanism of action in long-term breast cancer control.

Gray said the study was motivated by experiences gained from an OHSU Knight Cancer Institute clinical program called SMMART, or Serial Measurements of Molecular and Architectural Responses to Treatment. Serial biopsies from patients with metastatic cancer in SMMART suggested that certain drug combinations could modify the tumor microenvironment to boost antitumor activity.

“In many cases, there are no clinical trials supporting the utility of drug combinations predicted to increase TME-mediated antitumor activity on the bases of data from the SMMART analyses,” Gray wrote in a commentary published with the study. “As a consequence, it is difficult to apply novel mechanistically based drug combinations in individual patients. The present study was initiated to test the possibility that a MIMA-like approach would provide sufficient information to justify use of novel drug combinations in individual patients.”

Further reading:

A multiplex implantable microdevice assay identifies synergistic combinations of cancer immunotherapies and conventional drugs by Zuzana Tatarova, Dylan C. Blumberg, James E. Korkola, Laura M. Heiser, John L. Muschler, Pepper J. Schedin, Sebastian W. Ahn, Gordon B. Mills, Lisa M. Coussens, Oliver Jonas and Joe W. Gray. Nature Biotechnology (July 4, 2022)

Identifying drug combinations that enhance treatment responses mediated by the tumor microenvironment by Zuzana Tatarova, Oliver Jonas, and Joe W. Gray. Nature Biotechnology (July 4, 2022)

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