Data from Novel Oral mTORC1/2 Inhibitor TAK-228 Has Synergistic Antitumor Effects When Combined with Paclitaxel or PI3Kα Inhibitor TAK-117 in Preclinical Bladder Cancer Models

Abstract

<div>Abstract<p>Advanced bladder cancer is associated with a poor prognosis and limited treatment options. The PI3K/AKT/mTOR pathway is frequently activated in this disease and can be a potential therapeutic target for treatment intervention. We studied the antitumor efficacy of a new targeted therapy, TAK-228 (oral mTORC1/2 inhibitor), in preclinical models of bladder cancer. We evaluated the effects of TAK-228 in combination with a PI3Kα inhibitor (TAK-117) or with chemotherapy (paclitaxel). We used six bladder cancer cell lines and <i>in vivo</i> xenografts models. TAK-228 strongly inhibited cell proliferation <i>in vitro</i>, and reduced tumor growth and angiogenesis <i>in vivo</i>. Three possible biomarkers of response to TAK-228 (basal levels of 4E-BP1, p-4E-BP1/4E-BP1 ratio, or eIF4E/4E-BP1 ratio) were identified. The combination of TAK-228 and TAK-117 had synergistic effects <i>in vitro</i> and <i>in vivo</i>. Furthermore, TAK-228 demonstrated greater efficiency when combined with paclitaxel. TAK-228 also showed <i>ex vivo</i> activity in tumor tissue from patients with treatment-naïve bladder cancer. TAK-228 is a promising investigational agent that induces a strong effect on cell proliferation, tumor growth, and angiogenesis in bladder cancer models. High synergistic effects were observed with TAK-228 combined with a PI3K inhibitor or with chemotherapy. These results are currently being investigated in a clinic trial of TAK-228 plus paclitaxel in patients with metastatic bladder cancer (NCT03745911).</p>Implications:<p>Strong synergistic effects were observed when combining TAK-228 with TAK-117 (a PI3Kα inhibitor) or with paclitaxel chemotherapy. A phase II study at our institution is currently evaluating the efficacy of TAK-228 combined with paclitaxel in patients with metastatic bladder cancer.</p></div>

Pilot clinical trial and phenotypic analysis in chemotherapy-pretreated, metastatic triple-negative breast cancer patients treated with oral TAK-228 and TAK-117 (PIKTOR) to increase DNA damage repair deficiency followed by cisplatin and nab paclitaxel

“…This combination, referred to as "PIKTOR", is hypothesized to achieve greater inhibition of the PI3K/AKT pathway than either agent alone (20). Indeed, synergistic effects of TAK-228 and TAK-117 at their respective IC50s have been shown to reduce PI3K/AKT/mTOR (PAM) pathway activation, activate autophagy, and induce cell cycle arrest (21). Inhibition of PI3K has been shown to induce a HRD-like state in BRCA-wildtype TNBC (8,22).…”