**5. AKT inhibitors in cancer therapy**

[74]. Additional clinical evaluation of this PI3K inhibitor is ongoing in phase I/II studies

Pictilisib (GDC-0941) is another potent, selective, and orally bioavailable inhibitor of pan-class I PI3K. In biochemical assays, pictilisib demonstrates selectivity over a large panel of protein kinases and PI3K family kinases, including mTOR and DNA-dependent protein kinase (DNA-PK) [75]. Interestingly, pictilisib induces apoptosis in a subset of human tumor cell lines and potently inhibited tumor growth in xenograft models, including those with mutations in PI3K, PTEN, and K-Ras [76]. Significant *in vivo* antitumor activity has also been observed when administered orally in combination with other anticancer drugs, for example, docetaxel and

In a first-in-human phase I study of pictilisib in sixty patients with advanced solid tumors, the most frequently reported drug-related adverse events were nausea, fatigue, and rash [81]. Importantly, one patient with V600E BRAF-mutant melanoma and another with platinumrefractory ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response [81]. Pictilisib is currently under evaluation in several phase I/II clinical trials, mainly in non-small cell lung cancer and breast cancer (NCT01918306, NCT01740336,

One strategy to achieve significant pathway inhibition clinically with tolerable adverse effect profile is the use of isoform-specific PI3K inhibitors. As aforementioned, each isoform has distinct role in normal physiological processes and disease (Table 1). PI3K catalytic subunit p110α is predominantly responsible for mediating growth factor signaling from receptor tyrosine kinases and is a frequent genetic driver (*PIK3CA* mutations) in several cancers [82]. However, p110α is dispensable for PI3K pathway activation in tumors lacking PTEN. Thus, these cells depend largely on p110β to activate the pathway [82,83]. Preclinical tests showed that p110β-selective inhibitors had a significantly greater activity in cell lines with PTEN null than in those with PTEN intact, although, some PTEN-intact cell lines were sensitive and a number of cells lines lacking PTEN were resistant [84]. GSK-2636771 is a PI3K p110β-selective inhibitor currently in phase I studies in subjects with advanced solid tumors with PTEN deficiency (NCT01458067). Moreover, PI3Kδ is predominantly expressed in leukocytes and control immune responses [85]. Idelalisib (CAL-101), a highly specific PI3Kδ inhibitor, was the

Alpelisib (NVP-BYL719) is an oral inhibitor that selectively targets PI3K p110α equipotent against the wild type and the most common somatic mutations of p110α [87]. NVP-BYL719 has been the first PI3Kα-selective inhibitor to enter in clinical trials after positive preclinical investigations. *In vivo* studies have demonstrated dose-dependent antitumor activity of NVP-BYL719 in PIK3CA-mutant or PIK3CA-amplified tumor xenograft models, such as ovarian, breast, and head and neck cancers [88, 89]. Preliminary results of phase I study performed in patients with advanced solid tumors carrying *PIK3CA* gene alterations demonstrated that NVP-BYL719 has a favorable safety profile with manageable toxicities, as hyperglycemia, nausea, diarrhea, decreased appetite, vomiting, and fatigue [90]. To date, more than fifteen clinical trial is ongoing in order to evaluate the combination of NVP-BYL719 with several agents, such conventional cytotoxic drugs (paclitaxel, cisplatin, and irinotecan) and target

first isoform-specific PI3K inhibitors approved for cancer treatment [86].

(NCT01587040).

136 Updates on Cancer Treatment

MEK inhibitor U0126 [77-80].

NCT01493843, and NCT00974584).

AKT inhibitors constitute another class of drugs that has gained recent interest. As discussed previously, AKT is involved in the regulation of various signaling downstream pathways involved in cell survival, growth, proliferation, metabolism, and angiogenesis. AKT inhibition promotes decreasing cancer cell survival by preventing signal transduction through its downstream effectors. In addition, targeting AKT is an interesting pharmacological approach due to the AKT activation in consequence of the feedback loop release when mTOR is inhibited.

AKT inhibitors can be grouped into three classes, including lipid-based phosphatidylinositol (PI) analogs, ATP-competitive inhibitors (catalytic inhibitors), and allosteric inhibitors. To date, the most developed inhibitor of AKT is perifosine (KRX-0401), a lipid-based inhibitor. Perifosine is an allosteric inhibitor that targets the PH domain of AKT, thereby preventing its translocation to the plasma membrane required for pathway activation [99]. Perifosine has demonstrated great efficacy *in vitro* and *in vivo* against several human cancers such as breast, osteosarcoma, ovarian, multiple myeloma, leukemia, and glioma [100,101]. Additional *in vitro* data demonstrate synergistic effects of perifosine and traditional chemotherapeutic agents such as paclitaxel and cisplatin in ovarian cancer [102,103], etoposide in leukemia cells [104], doxorubicin in multiple myeloma cells [105], and gemcitabine in pancreatic cells [106].

Despite these encouraging preclinical studies, results from phase I/II clinical trials of perifosine as single agent in a various tumor types (metastatic breast cancer, metastatic head and neck cancer, locally advanced soft tissue sarcoma, prostate cancer, and metastatic

In behalf of the poor efficacy of perifosine as a single agent observed in most tumor types evaluated thus far, efforts have been made to combine this drug with target agents and chemotherapy. Phase I studies have now confirmed the safety of these combinations with different agents, including sorafenib in patients with Hodgkin lymphoma and taxanes in highgrade epithelial ovarian cancer [112,113]. Currently, one clinical trial with perifosine is recruiting patients, a phase II study with perifosine and temsirolimus in patients with malignant gliomas (NCT02238496).

GSK-690693 is a potent ATP-competitive AKT inhibitor selective for all three AKT isoforms versus the majority of kinases assessed by biochemical tests [114]. GSK690693 displayed antiproliferative activity *in vitro* and *in vivo* models of ovarian, breast, and prostate cancer [114]. The compound has entered phase I trials for refractory hematologic malignancies but was withdrawn prior to enrolment (NCT00666081).
