The BWH team's approach consisted of combining two targeted agents, the mTOR inhibitor rapamycin, which suppresses tumor growth, and the HSP90 inhibitor IPI-504 from
Infinity Pharmaceuticals, which generates a specific type of stress within cancer cells. Individually, the drugs did not promote significantly tumor regression, but together, the drugs caused significant tumor regression in both cancer types when tested in mice. Cichowski says they had previously discovered rapamycin's ability to halt tumor growth, though it didn't lead to shrinking, and decided to find agents to combine with it, settling on IPI-504 in the hopes that "it might capitalize on specific vulnerabilities of these cancer cells."
"These agents synergize by promoting irresolvable ER [endoplasmic reticulum] stress, resulting in catastrophic ER and mitochondrial damage," the paper notes. "This process is fueled by oxidative stress, which is caused by IPI-504-dependent production of reactive oxygen species, and the rapamycin-dependent suppression of glutathione, an important endogenous antioxidant. Notably, the mechanism by which these agents cooperate reveals a therapeutic paradigm that can be expanded to develop additional combinations."
"It's like hitting the tumor cell from two different angles," said Cichowski in a press release. "Using one drug to put on the brakes and another to apply stress to an already stressed cancer cell, which ultimately triggers its self-destruction."
The effectiveness of the bi-frontal attack is obvious, as the paper notes that "on average tumors shrank 45 percent; however, some tumors regressed more than 75 percent and remaining masses were largely comprised of hemorrhage and cellular debris. Maximal effects were observed within 10 days, although significant tumor regression was detected in three days…when animals were successfully treated for longer duration, tumors did not re-grow. One animal survived 107 days after tumor development with no evidence of relapse, surviving more than 10 times as long as control animals."
The researchers are already moving forward with the next steps in their work.
"We are trying to identify biomarkers/genetic alterations that may predict efficacy," says Cichowski. "We are also trying to capitalize on this strategy to develop other thematically similar combinations."
In addition, the studies have led to testing a drug combination that is now in a Phase I clinical trial, specifically for KRAS-mutant lung cancer. Cichowski notes that the identification of the combination "sets the stage for developing other combinations and may also prove effective in other cancers through further research." Cichowski says that there might be other traditionally unresponsive cancers that could benefit from similar drug combination, "but they need to be empirically tested."
In addition to Cichowski, additional authors of the paper include Thomas De Raedt, Zandra Walton, Jessica L. Yecies, Danan Li, Yimei Chen, Clare F. Malone, Phelia Maertens, Seung Min Jeong, Roderick T. Bronson, Valerie Lebleu, Raghu Kalluri, Emmanuel Normant, Marcia C. Haigis, Brendan D. Manning, Kwok-Kin Wong and Kay F. Macleod.
The
National Cancer Institute and the Ludwig Center at
Dana-Farber/Harvard Cancer Center both provided funding for the research.
