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Study Supports Early Investigation of Infinity's PGx-Guided HSP90/mTOR Inhibitor Dual Attack Regimen

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By Turna Ray

Infinity Pharmaceuticals, with the help of research led by Brigham and Women's Hospital, is in the early stages of studying the investigational drug IPI-504 in combination with Novartis' cancer treatment Afinitor as a pharmacogenomically guided regimen for patients with KRAS-mutated non-small cell lung cancer.

"While significant progress has been made in developing therapies for lung cancers that harbor a mutation in the EGFR gene, to date there are no effective target therapies for KRAS mutant lung cancer, which is more prevalent," said Karen Cichowski, associate professor of genetics at BWH and lead author of a study published this week in Cancer Cell that provides the basis for Infinity's investigational combination treatment.

The study conducted by Cichowski and colleagues suggests that a regimen containing an HSP90 inhibitor, such as IPI-504, and an mTOR inhibitor, like Afinitor, may be effective in zapping Ras-driven tumors, which are often resistant or refractory to conventional treatments. This research may ultimately fulfill an unmet medical need, given that cancer treatments such as Erbitux and Vectibix are now indicated to exclude patients with KRAS mutations. Approximately 25 percent of lung cancer tumors exhibit mutations in KRAS, which is part of the Ras gene family.

In the Cancer Cell study, the researchers found that IPI-504 in combination with the mTOR inhibitor rapamycin was effective in regressing tumors in mice with neurofibromatosis type 1-deficeint malignancies affecting the nervous system and KRAS/p53 mutant lung cancer. According to the study authors, this combination worked because while the mTOR inhibtiro rapamycin suppressed tumor growth weakening the cancer cell, the HSP90 inhibitor IPI-504 induced unfolded proteins to accumulate in the endoplasmic reticulum of cells, causing them to self-destruct under accumulating stress.

"The mechanism by which these agents cooperate reveals a therapeutic paradigm that can be expanded to develop additional combinations," Cichowski et al. concluded in the paper. The National Cancer Institute and the Ludwig Center at Dana-Farber/Harvard Cancer Center provided funding for the study.

Infinity, a collaborator in the study, in July launched a Phase Ib/II trial investigating IPI-504 in combination with the mTOR inhibitor Afinitor in KRAS-mutated NSCLC patients. Afinitor is currently approved in the US as a treatment for kidney cancer, for brain tumors associated with a genetic condition called tuberous sclerosis, and for pancreatic neuroendocrine tumors.

The trial is slated for completion in June 2012. According to Cichowski, in the Phase Ib/II study, only patients with a KRAS mutation will be enrolled and will have their tumors sequenced for the KRAS gene. For the primary endpoint, researchers will assess patients' overall response rate to the combination therapy; secondary measures include progression-free survival, time to progression, and overall survival.

Infinity's trial design for the IPI-504/Afinitor combo is guided by the knowledge gained from the study published in Cancer Cell, in which the researchers initially tested rapamycin in malignant peripheral nerve sheath tumor models and found that it only stopped cancer cells from multiplying. To bolster the efficacy of the treatment, they decided to pair an mTOR inhibitor with an HSP90 inhibitor to induce proteotoxic stress that would actually kill cancer cells.

In two models of mice with NF1-deficient nervous system malignancies and KRAS/p53-mutated NSCLC, researchers investigated the efficacy of IPI-504 as a single agent and in combination with rapamycin. While IPI-504 could not promote tumor regression as a single agent, tumors shrank 49 percent when the drug was combined with the mTOR inhibitor. The regimen also shrank tumors and "significantly prolonged survival," the study authors wrote in the paper. The tumors in mice began to regress within three to five days of starting the dual therapy and researchers reported no long-term toxicities after 50 days of treatment.

According to Cichowski et al., this is the first time any targeted agents have been shown to cause tumor regression in genetically engineered models of either of these aggressive cancers. "Given that these human cancers are generally refractory to standard therapies, there is an urgent need to develop improved treatments," the study authors wrote, concluding that the work has "identified a promising therapeutic strategy for these two aggressive malignancies."

Researchers estimate that 15 percent of all human cancers harbor mutations in Ras genes, most commonly occurring in lung, colon, and pancreatic cancers. Cichowski told PGx Reporter that she and her colleagues chose to study NF-1 deficient malignancies of the nervous system and KRAS/p53-mutated lung cancer because they were both driven by Ras. Furthermore, rapamycin had already shown tumor suppressor activity in NF1-mutant tumors.

"Because these nervous system tumors harbor mutations in NF1 (which normally turns off Ras) we thought IPI-504 might work on Ras mutant tumors as well," Cichowski said in an e-mail, adding that the study authors then decided to also evaluate KRAS/p53 mutant lung cancer because these tumors were genetically similar to the NF1/p53cancer model in terms of harboring Ras and p53 mutations.

Cichowski et al. note in the paper that it will be important to conduct additional trials to see if IPI-504 and rapamycin can be efficacious in other Ras-driven tumors, other mTOR-driven tumors, or other tumors that exhibit high endoplasmic reticulum stress. Additionally, study authors note that RAS, NF1, and possibly other genes that impact the mTOR pathway can serve as markers for response for the combination regimen.

"This therapy may very well work in other Ras-driven tumors such as colon and pancreatic cancer, but needs to be empirically tested. It may also work in other genomically unstable aggressive cancers," Cichowski said. "We are currently trying to develop genetic and molecular biomarkers that may predict efficacy."

The study also serves as a foundation for additional research combining different mTOR inhibitors and HSP90 inhibitors, or combining different agents that promote proteotoxic stress. Most importantly, the study proves that attacking the different molecular features of cancer cells through a combination of drugs can be a better strategy than using single targeted agents when it comes to personalizing treatment for resistant or refractory cancers.

"The potential utility of these agents may be overlooked if they are assessed exclusively as monotherapies in genetically heterogeneous tumors, where individually they may exhibit minimal activity," Cichowski et al. wrote in the paper. "Indeed, none of the single agents investigated in this study exerted a cytotoxic response when administered individually."

Several drug companies have HSP90 inhibitors in various stages of development in their pipelines, and are exploring them as potential treatments for molecularly defined subsets of cancer patents who have developed resistance to drugs such as ALK inhibitors or EGFR inhibitors. Although Cichowski and her colleagues are currently working with Infinity on IPI-504, she is hopeful that other drug developers will also express an interest in exploring a similar strategy.

"I am expecting that we will be contacted" by other drug firms "now that the study has been published," she said.


Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at tray [at] genomeweb [.] com.

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