A research team co-led by scientists at The Wistar Institute has combined a promising cancer therapy with a molecule that targets tumors to treat cancer more effectively. The new approach, they suggest, could be a way to deliver treatment directly to tumors at higher doses, while reducing side effects in healthy tissue. The novel chimeric small molecule, designated NN-01-195, combines an aurora kinase A (AURKA) inhibitor with an HSP90-binding construct that targets the molecule to tumors. The team reported promising results with the molecule in lab-grown cells and in animal models.
“An Aurora kinase A (AURKA) inhibitor is viewed as a lethal synthetic molecule in cancer therapy, but the problem is you can’t dose it high enough, because then it starts to spill over and target normal cells, causing toxicity,” said coauthor Joseph Salvino, PhD, professor in the Molecular and Cellular Oncogenesis Program at the Ellen and Ronald Caplan Cancer Center, and scientific director of The Wistar’s Molecular Screening & Protein Expression Facility. “By using this cancer-targeting approach, we can direct this molecule, which is already in clinical use, to cancer cells, increasing its exposure in the tumor itself.”
Salvino is co-author of the researchers published paper in Molecular Cancer Therapeutics, in a paper titled “NN-01-195, a novel conjugate of HSP90 and AURKA inhibitors, effectively targets solid tumors,” in which they concluded “The work presented here demonstrates that NN-01-195 is a promising pilot compound for a new strategy of targeting AURKA.”
“Aurora kinase A (AURKA) regulates cell cycle progression into and through mitosis, and its expression is “… highly elevated in many sold tumors …” the authors wrote. “As overexpression of AURKA in cancer cells is common and associated with mitotic defects and aneuploidy, small molecule inhibitors of AURKA have been developed as candidate therapies for cancer.” However, the team pointed out, while this molecule has shown promise in clinical trials, it has also caused toxic side effects that limited its use. “A strategy to selectively target AURKA inhibitors to tumor tissue would be predicted to greatly increase the clinical utility of these drugs.”
The new chimeric molecule takes two existing molecules and attaches them together like LEGO blocks to make a small molecule drug conjugate, NN-01-195. One half of the conjugate is a derivative of the clinically used Aurora kinase A (AURKA) inhibitor, VIC-1911. The second half is a molecule that binds to HSP90, which cancer cells produce to help them survive stress. By targeting HSP90, which is found at high levels in cancer cells, researchers hoped to show that they could concentrate the compound within the tumor, preferentially over healthy tissue.
“When drugs fail in the clinic, 50% of the time it’s because of poor exposures in the tumor, due to pharmacokinetic problems,” or the body’s ability to absorb or interact with a drug, Salvino explained. “Our approach will take an existing compound and improve its pharmacokinetic properties, enhancing its exposures in the tumor.”
In a proof-of-concept study the researchers demonstrated that the new chimeric molecule successfully binds to both the AURKA and HSP90 proteins. Tests with NN-01-195 in cell samples taken from multiple cancer types, including head and neck, lung, and melanoma, demonstrated that it stopped the cancer cells from dividing and replicating, eventually causing the cells to die.
When tested the in preclinical animal models NN-01-195 concentrated inside the tumors at levels sometimes 10 times higher than when the original AURKA inhibitor was used on its own. “We show that this compound maintains binding activity for HSP90 and AURKA, and AURKA inhibitory activity, and selectively concentrates in xenograft tumors in vivo,” the researchers stated. The compound also stayed in the tumor for much longer, and was still active 24 hours after being injected, while the original inhibitor was no longer detectable. “Analysis of signaling in recovered xenograft tumors indicated NN-01-195-treated cells effectively maintained AURKA inhibition over several weeks of in vivo treatment,” the investigators reported.
NN-01-195 was in addition well tolerated in preclinical models, with no significant toxicity. When the researchers combined the new molecule with inhibitor of the G2/M checkpoint protein WEE1, the two together were even more effective in controlling tumor growth. “Importantly, in combination with a WEE1 inhibitor, NN-01-195 was well tolerated, and more effective than VIC-1911 in controlling xenograft growth,” they noted. “In conclusion, this study provides evidence to support the rationale for stable bi-functional HSP90-AURKA conjugates to improve efficacy due to increased drug exposure in the tumor tissue, and to improve safety by minimizing mechanism-based toxicity on normal tissues.”
Salvino suggests that in addition to the cancers tested in the initial study, the new compound should have broad application to many other types of cancer. Next, researchers plan to apply their approach to different molecules and types of cancer. They also want to develop the new chimeric molecule into a formulation that can be given orally.
