Results from a Phase I trial shows that a novel oral cancer drug, ARQ-092 (ArQule, Inc), inhibits the AKT pathway and has a manageable safety profile in patients with a variety of advanced solid tumors. Researchers confirmed this during the Annual Meeting of the American Association for Cancer Research(AACR), held in Washington, D.C., April 6-10, 2013.

?AKT is a signal transduction pathway crucially involved in the growth, survival and metabolism of cancer cells,? said Mansoor N. Saleh, M.D., professor of medicine at the University of Alabama Comprehensive Cancer Centerin Birmingham and director of research at Georgia Cancer Specialists in Atlanta.

For example, breast tumor cells with PI3K mutations or HER2 amplification have been shown to be dependent on AKT signaling. PTEN null cells or cells with inactivating mutations of PTEN have also been shown to be dependent on AKT signaling. [1]

?Many of the signaling pathways disrupted by commonly seen cancer-causing mutations merge into the AKT pathway. In addition, the AKT pathway is often amplified and mutated in patients who relapse following initial therapy.”

Regulating growth and survival
In both normal and cancer cells, AKT, also known as the serine/threonine kinase PKB, regulates growth and survival mechanisms by phosphorylating a large number of substrates. Most of the stimuli that induce these responses activate PI3K, a lipid kinase that catalyzes the synthesis of the membrane phospholipid PtdIns-3,4,5-P3 from PtdIns-4,5-P2, effectively recruiting AKT to the plasma membrane by direct interaction of PtdIns-3,4,5-P3 with the AKT pleckstrin homology domain. A further full activation of AKT also requires phosphorylation of two conserved residues, Thr308 and Ser473. Once phosphorylated and active, AKT relocalizes to several subcellular locations where it phosphorylates proteins and activate a number of downstream kinases such as Forkhead transcription factors (Foxo1, Foxo3), GSK3?, GSK3?, BAD, and MDM2, PRAS40, mTOR, and TSC2/TSC1, some of which contribute to antiapoptotic signaling. [1] [2]

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Phosphorylation of GSK3 allows accumulation of cyclin D1 and subsequent increase in cell proliferation. Furthermore, phosphorylation of Foxo proteins also induces cell survival and proliferation. Phosphorylation of PRAS40 and mTOR induce cell growth by activating p70S6 kinase and suppressing PHAS-I.

A potential treatment target
When taken together, the available data suggests that pharmacological inhibition of AKT directly impacts cell survival, proliferation, and protein synthesis in AKT pathway-driven cancers. ?This means that the AKT pathway is a potential treatment target for numerous cancer types, either at diagnosis or when they become resistant to initial therapies.?

Saleh and his colleagues tested the safety and activity of ARQ-092 in patients with a broad range of advanced or metastatic solid tumors, including colorectal, endometrial and neuroendocrine cancers. They assigned patients in the first cohort to a dose of 10 mg every other day and enrolled subsequent patients into cohorts of three to six patients who were assigned to a dose escalation schedule with the drug. ?This class of agents has two common toxicities, namely skin toxicity and hyperglycemia, a rise in blood sugar levels,? Saleh said. ?Based on data presented with other AKT inhibitors, skin toxicity has been the dose-limiting side effect and often resulted in drug discontinuation.?

No dose-limiting skin toxicity
To date, Saleh and colleagues have observed no dose-limiting skin toxicity. In addition, they have observed that with ARQ 092, blood sugar levels rise before patients experience skin toxicity, and they have been able to treat the hyperglycemia, thus allowing the patients to continue on the experimental drug.

?When we see hyperglycemia, we know that the drug is active in patients,? Saleh said. ?We can ameliorate the high blood sugar, potentially allowing us to achieve drug levels that will be therapeutically active.?

Maximum tolerated dose
Currently, the maximum tolerated dose has not been reached in this ongoing trial, but Saleh and colleagues have confirmed that the 80-mg dose once a day is not well tolerated. Seven patients have remained stable on the drug for more than four months. Four patients with advanced and refractory solid tumors have had stable disease for longer than six months, according to Saleh.

Once the maximum tolerated dose is identified, Saleh and colleagues plan to test the drug for efficacy. ?We will also explore the drug activity in patients with a high level of AKT in the tumor to identify the patient populations that can robustly benefit from our treatment,? he said. [3]

Earlier this month, ArQule regained worldwide rights to develop and commercialize the lead compound and other drugs covered under its AKT cancer drug collaboration with Daiichi Sankyo. This reversion of rights followes Daiichi Sankyo terminating a license and co-commercialization agreement for ARQ-092 with ArQule which was originally reached in November 2011. The collaboration is based on the ArQule Kinase Inhibitor Platform (AKIP?).

For more information:
[1] Chan TCK, Lapierre JM, Ashwell MA, France DS, Chen CR, Cornell-Kennon S. et al. Discovery and Characterization of ARQ-092, an ATP-independent, Potent and Selective Inhibitor of AKT Kinases. [Download Poster]
[2] Toker A, Yoeli-Lerner M. AKT Signaling and Cancer: Surviving but not Moving On. Cancer Res April 15, 2006 66; 3963

Clinical trial
[3]NCT01473095 – Phase 1 Dose Escalation Study of ARQ-092 in Adult Subjects With Advanced Solid Tumors

Photo courtesy:GCS/Georgia Cancer Specialists

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