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

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 PI3Ka inhibitor (TAK-117) or with chemotherapy (paclitaxel). We used six bladder cancer cell lines and in vivo xenografts models. TAK-228 strongly inhibited cell proliferation in vitro, and reduced tumor growth and angiogenesis in vivo. 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 in vitro and in vivo. Furthermore, TAK-228 demonstrated greater efficiency when combined with paclitaxel. TAK-228 also showed ex vivo activity in tumor tissue from patients with treatment-na€ ve 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). Implications: Strong synergistic effects were observed when combining TAK-228 with TAK-117 (a PI3Ka 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.

Resveratrol, curcumin, paclitaxel and miRNAs mediated regulation of PI3K/Akt/mTOR pathway: go four better to treat bladder cancer

“…Resveratrol, curcumin and paclitaxel are bioactive molecules with well documented anti-cancer properties. Their interactions with different genes have established them as a modulator of various cancers [ 27 – 29 ]. These compounds help in the regulation of the oxidative stress.…”

Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer

“…Preclinical models of efficacy, safety and pharmacokinetics (PK) of sapanisertib have largely relied on daily dosing. [19][20][21][22][23] Investigation of different dosing schedules in preclinical efficacy models has demonstrated commensurate tumour growth inhibition with administration of sapanisertib in daily or intermittent dosing schedules. [19][20][21][22][23] These preclinical data generally indicated that efficacy was related to total exposure (i.e.…”

Gemcitabine and Selected mTOR Inhibitors in Uterine Sarcomas and Carcinosarcoma Cells- an Isobolographic Analysis

“…The most important is using only 2D models of uterine sarcomas and carcinosarcoma, such models are easily reproducible and allow to perform isobolographic analysis of relations between tested substances, but on the other hand do not fully reflect behaviour of tumours in vivo . Secondly, the reported project do not include any mechanistic research, partially the activity mechanisms of used compounds were previously described 4 , 5 , 5 , 7 , 26 , 29 , 30 , 33 , 35 but further studies aimed to describe mechanisms of cellular response to combined treatment are strongly indicated.…”

“…The mechanism of overcoming rapamycin resistance by MLN was revealed by Rodik-Outmezguine et al 4 Further studies confirmedactivity of this substance in i.a. pancreatic and bladder cancer cell lines and xenografts 6 , 7 . At present, MLN undergoes clinical trials in many indications, including solid tumours.…”