Beginning next year, Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital will initiate a new early phase clinical trial aimed at stopping bone loss and cancer progression in patients with metastatic breast cancer (MBC). The trial is based on promising laboratory research conducted at the School of Medicine that showed a specific MK2 inhibitor not only reduced tumor growth but also reduced bone destruction.
“In the breast cancer setting, the most common site of metastasis is the bone,” says Washington University cancer biologist Sheila Stewart, PhD, the Gerty Cori Professor and Vice Chair of the Department of Cell Biology and Physiology. “We have identified a specific molecular pathway that is active in the metastatic setting and when we blocked this pathway in a normal cell, it stopped tumor growth and bone loss. It’s a one-two punch.”
Stewart’s lab studies showed how changes in noncancerous cells, called stroma, enable tumor cell growth. Her focus is on interrupting that process to prevent cancer progression. To bring this laboratory finding to the clinic, Stewart established a collaboration with Aclaris Therapeutics, Inc., which is developing MK2 inhibitors. With data generated in Stewart’s lab, Aclaris provided its investigational MK2 inhibitor, ATI-2231, for laboratory testing as a cancer therapeutic.
Recently, her lab found that by blocking the p38MAPK-MK2 pathway in stromal cells [using ATI-2231], tumor growth was limited, and bone loss was reduced. If the pathway was activated, however, it promoted breast cancer metastasis and subsequent bone loss.
Stewart’s subsequent findings with ATI-2231 are significant because the standard treatments for MBC, such as chemotherapy, do not address the tumor cell microenvironment and often lose effectiveness quickly due to cancer cell developing adaptive resistance mechanisms. The novel approach of treating cancer by targeting the stroma has the potential to allow longer duration of disease control. Bone metastasis is particularly common in patients with metastatic hormone receptor positive/HER-2-negative breast cancer. Patients often develop bone fractures as the cancer progresses to the bone.
“We have two medications, bisphosphonates and denosumab, which are FDA-approved to help prevent bone fractures; however, these drugs have significant toxicities over time, and they don’t control tumor growth in the metastatic setting,” says Washington University medical oncologist Cynthia Ma, MD, PhD, at Siteman Cancer Center.
This is why Ma and her colleague, Katherine Clifton, MD, also a Washington University medical oncologist at Siteman Cancer Center, are eager to begin a first-in-human Phase I/II trial that will first evaluate the safety and dosing levels of ATI-2231 in patients with advanced solid malignancies. ATI-2231 then will be evaluated for its bone protective and anti-tumor effect in breast cancer patients with bone metastasis. Used in combination with a chemotherapy agent, capecitabine, it is hoped that the exciting laboratory results that stopped cancer and bone loss will be duplicated in humans.
“Despite all the improvements in various targeted drugs, metastatic HER+/HER2 breast cancer remains incurable,” says Ma. “The transformative preclinical work that Sheila and her lab have provided is the foundation for this clinical trial, and we are eager and hopeful that we may be able to translate their findings into the clinical setting.”
Clifton will lead the Phase I trial at Washington University School of Medicine. Up to 48 patients will be enrolled in the first year of the study. Phase II, which will examine dosing levels and outcomes, will enroll 120 patients. The Phase I/II trial is partially funded by a multi-million-dollar Level 3 Breakthrough Award from the Department of Defense. Principal investigator is Stewart, with Ma as a co-principal investigator.
In addition to Washington University, there are two other participating academic institutions. Aclaris Therapeutics will provide the study drug and is partially funding the Phase I portion of the trial.
“This research is pretty provocative,” notes Stewart, who also serves as Associate Director for Basic Sciences at Siteman Cancer Center. “It’s fair to say that this is only the beginning of our approaches to put a stranglehold on cancer cells by both reducing their ability to grow and to damage bone.”
The clinical trial for ATI-2231 is currently in protocol development and will the early phase plans to open in 2023 subject to regulatory approval for patients with advanced solid malignancies, followed by patients with advanced hormone receptor positive/HER-2-negative breast cancer. The drug will be manufactured by Aclaris Therapeutics, Inc.
To view the list of active clinical trials at Siteman, go to siteman.wustl.edu/clinical-trials.