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BMC Cancer Jun 2017Ridaforolimus is a mammalian target of rapamycin inhibitor that has activity in solid tumors. Paclitaxel and carboplatin have broad antineoplastic activity in many...
BACKGROUND
Ridaforolimus is a mammalian target of rapamycin inhibitor that has activity in solid tumors. Paclitaxel and carboplatin have broad antineoplastic activity in many cancers. This phase I trial was conducted to determine the safety profile, maximal tolerated dose, and recommended phase II dose and schedule of oral ridaforolimus combined with paclitaxel and carboplatin in patients with solid tumor cancers.
METHODS
Eligible patients with advanced solid tumor cancers received oral 10 to 30 mg ridaforolimus daily for 5 consecutive days per week combined with intravenous paclitaxel (175 mg/m) and carboplatin (area under the curve [AUC] 5-6 mg/mL/min) in 3-week cycles. A standard 3 + 3 design was used to escalate doses, with predefined changes to an alternate dosing schedule and/or changes in carboplatin AUC doses based on dose-limiting toxicity (DLT). Secondary information was collected regarding response and time to progression. Patients were continued on treatment if therapy was tolerated and if stable disease or better was demonstrated.
RESULTS
Thirty-one patients were consented, 28 patients were screened, and 24 patients met eligibility requirements and received treatment. Two patients were replaced for events unrelated to drug-related toxicity, resulting in 22 DLT-evaluable patients. Two grade 4 DLTs due to neutropenia were observed at dose level 1. The next cohort was changed to a predefined alternate dosing schedule (days 1-5 and 8-12). DLTs were neutropenia, sepsis, mucositis, and thrombocytopenia. The most common adverse events were neutropenia, anemia, thrombocytopenia, fatigue, alopecia, nausea, pain, and leukopenia. Twenty-four patients received a median of 4 cycles (range, 1-12). Evaluable patients for response (n = 18) demonstrated a median tumor measurement decrease of 25%. The best response in these 18 patients included 9 patients with partial response (50%), 6 with stable disease (33%), and 3 with progressive disease (17%). Thirteen of these patients received treatment for 4 or more cycles.
CONCLUSIONS
Treatment with ridaforolimus combined with paclitaxel and carboplatin had no unanticipated toxicities and showed antineoplastic activity. The recommended phase II dose and schedule is ridaforolimus 30 mg (days 1-5 and 8-12) plus day 1 paclitaxel (175 mg/m) and carboplatin (AUC 5 mg/mL/min) on a 21-day cycle.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01256268 (trial registration date: December 1, 2010).
Topics: Administration, Oral; Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia; Paclitaxel; Research Design; Sirolimus; Thrombocytopenia
PubMed: 28595616
DOI: 10.1186/s12885-017-3394-2 -
Breast Cancer Research and Treatment Jun 2017Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67 > 15%).
METHODS
This randomized, multicenter, international, phase II study enrolled postmenopausal women with advanced ER-positive breast cancer previously treated with a nonsteroidal aromatase inhibitor (NCT01234857). Patients were randomized to either oral ridaforolimus 30 mg daily for 5 of 7 days (once daily [qd] × 5 days/week) plus intravenous dalotuzumab 10 mg/kg/week or oral exemestane 25 mg/day, and stratified by Ki67 status. Due to a high incidence of stomatitis in the ridaforolimus-dalotuzumab group, two sequential, nonrandomized, reduced-dose cohorts were explored with ridaforolimus 20 and 10 mg qd × 5 days/week. The primary endpoint was progression-free survival (PFS).
RESULTS
Median PFS was 21.4 weeks for ridaforolimus 30 mg qd × 5 days/week plus dalotuzumab 10 mg/kg (n = 29) and 24.3 weeks for exemestane (n = 33; hazard ratio = 1.00; P = 0.5). Overall survival and objective response rates were similar between treatment arms. The incidence of drug-related, nonserious, and serious adverse events was higher with ridaforolimus/dalotuzumab (any ridaforolimus dose) than with exemestane. Lowering the ridaforolimus dose reduced the incidence of grade 3 stomatitis, but overall toxicity remained higher than acceptable at all doses without improved efficacy.
CONCLUSIONS
The combination of ridaforolimus plus dalotuzumab was no more effective than exemestane in patients with advanced ER-positive breast cancer, and the incidence of adverse events was higher. Therefore, the combination is not being further pursued.
Topics: Adult; Aged; Androstadienes; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Disease-Free Survival; Female; Humans; Middle Aged; Protein Kinase Inhibitors; Receptors, Estrogen; Sirolimus; Stomatitis
PubMed: 28324268
DOI: 10.1007/s10549-017-4199-3 -
Advances in Biological Regulation May 2017Activation of PI3K/Akt/mTOR (mechanistic target of rapamycin) signaling cascade has been shown in tumorigenesis of numerous malignancies including glioblastoma (GB).... (Review)
Review
Activation of PI3K/Akt/mTOR (mechanistic target of rapamycin) signaling cascade has been shown in tumorigenesis of numerous malignancies including glioblastoma (GB). This signaling cascade is frequently upregulated due to loss of the tumor suppressor PTEN, a phosphatase that functions antagonistically to PI3K. mTOR regulates cell growth, motility, and metabolism by forming two multiprotein complexes, mTORC1 and mTORC2, which are composed of special binding partners. These complexes are sensitive to distinct stimuli. mTORC1 is sensitive to nutrients and mTORC2 is regulated via PI3K and growth factor signaling. mTORC1 regulates protein synthesis and cell growth through downstream molecules: 4E-BP1 (also called EIF4E-BP1) and S6K. Also, mTORC2 is responsive to growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases like Akt and SGK. mTORC2 plays a crucial role in maintenance of normal and cancer cells through its association with ribosomes, and is involved in cellular metabolic regulation. Both complexes control each other as Akt regulates PRAS40 phosphorylation, which disinhibits mTORC1 activity, while S6K regulates Sin1 to modulate mTORC2 activity. Another significant component of mTORC2 is Sin1, which is crucial for mTORC2 complex formation and function. Allosteric inhibitors of mTOR, rapamycin and rapalogs, have essentially been ineffective in clinical trials of patients with GB due to their incomplete inhibition of mTORC1 or unexpected activation of mTOR via the loss of negative feedback loops. Novel ATP binding inhibitors of mTORC1 and mTORC2 suppress mTORC1 activity completely by total dephosphorylation of its downstream substrate pS6K, while effectively suppressing mTORC2 activity, as demonstrated by complete dephosphorylation of pAKT. Furthermore, proliferation and self-renewal of GB cancer stem cells are effectively targetable by these novel mTORC1 and mTORC2 inhibitors. Therefore, the effectiveness of inhibitors of mTOR complexes can be estimated by their ability to suppress both mTORC1 and 2 and their ability to impede both cell proliferation and migration.
Topics: Antineoplastic Agents; Brain Neoplasms; Cell Movement; Cell Proliferation; Clinical Trials as Topic; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Indoles; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Neoplastic Stem Cells; PTEN Phosphohydrolase; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Purines; Signal Transduction; Sirolimus
PubMed: 28189457
DOI: 10.1016/j.jbior.2016.12.001 -
British Journal of Haematology Jun 2017It is widely demonstrated that the PI3K-AKT-mTOR signalling is critical in normal myeloid and lymphoid development and function. Thus, it is not strange that this... (Review)
Review
It is widely demonstrated that the PI3K-AKT-mTOR signalling is critical in normal myeloid and lymphoid development and function. Thus, it is not strange that this pathway is often deregulated in haematological tumours, providing a strong preclinical rationale for the use of drugs targeting the PI3K-AKT-mTOR axis in haematological malignancies. The main focus of this review is to examine the mammalian target of rapamycin (mTOR, also termed mechanistic target of rapamycin [MTOR]) signalling pathways and to provide a brief overview of rapalogs and second-generation mTOR inhibitors used to target its aberrant activation in cancer treatment. We will also discuss the results obtained with the use of these agents in patients with acute leukaemia, Hodgkin lymphoma, non-Hodgkin lymphomas, multiple myeloma and Waldenström macroglobulinaemia. Ongoing clinical trials in haematological malignancies that are investigating first- and second-generation mTOR inhibitors as single agents and as components of combination regimens are also presented.
Topics: Antibiotics, Antineoplastic; Clinical Trials as Topic; Everolimus; Hematologic Neoplasms; Humans; Phosphoinositide-3 Kinase Inhibitors; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 28146265
DOI: 10.1111/bjh.14529 -
Critical Reviews in Oncology/hematology Dec 2016mTOR inhibitors are widely used in different malignancies with several trials testing their efficacy and safety in gynecological malignancies. We aimed to review the... (Review)
Review
BACKGROUND
mTOR inhibitors are widely used in different malignancies with several trials testing their efficacy and safety in gynecological malignancies. We aimed to review the current evidence that support the expansion of using such drugs in the treatment of advanced gynecological cancers.
METHODS
A comprehensive systematic review of literature has been conducted to include prospective trials that used everolimus, temsirolimus or ridaforolimus in the management of gynecological cancers and have available efficacy and toxicity results.
RESULTS
A total of 23 studies including 980 patients were considered eligible for our review. Our review included 16 phase II and 7 phase I studies with the majority of patients having uterine cancers. Regarding Endometrial cancer, the CBR ranged from 21% to 60% and median PFS from 2.8 months to 7.3 months. In Ovarian cancers, CBR ranged from 24% to 50% and median PFS from 3.2 months to 5.9 months. In the single phase II study in cervical cancer the CBR was 61% and median PFS was 3.5 months. The toxicity profile was consistent with what was observed previously in other malignancies with fatigue, mucositis, and hematological toxicities being the most common adverse events observed.
CONCLUSION
mTOR inhibitors seem to be a promising option in the second line management of advanced gynecological cancers with best safety and efficacy outcomes when given as a single agent or in combination with hormonal treatment. More research is needed for better patient selection.
Topics: Endometrial Neoplasms; Female; Humans; Ovarian Neoplasms; Risk Factors; Signal Transduction; TOR Serine-Threonine Kinases; Uterine Cervical Neoplasms
PubMed: 27931828
DOI: 10.1016/j.critrevonc.2016.10.003 -
Anticancer Research Nov 2016Sarcoma carries a poor prognosis prompting the need for targeted therapies aimed at deregulated signaling pathways. These include the PI3K/Akt/mTOR pathway commonly...
BACKGROUND/AIM
Sarcoma carries a poor prognosis prompting the need for targeted therapies aimed at deregulated signaling pathways. These include the PI3K/Akt/mTOR pathway commonly up-regulated in malignancies attributed to loss of PTEN expression. However, PTEN status and activation state of PI3K/Akt/mTOR pathway have not been comprehensively studied in sarcoma. The aims of this study were to characterise PTEN and Akt expression in a panel of sarcoma cell lines and then to examine mTOR inhibition using ridaforolimus.
MATERIALS AND METHODS
PTEN genomic expression was analyzed using Sanger sequencing. PTEN, total Akt (tAkt) and phosphorylated Akt (pAkt) expression were quantified with western blot analysis. Antiproliferative effects of treatment regimens were designed using Chou & Talalay's isobologram and determined with crystal violet assay.
RESULTS
Four cell lines had wild-type PTEN (exons 2 to 8), with normal protein expression. The GCT cell line had a missense mutation in exon 6 (C>T), associated with loss of PTEN protein expression. Increased pAkt expression was found in all cell lines following epidermal growth factor (EGF) stimulation, indicating that wild-type PTEN expression in four cell lines did not inhibit constitutive activation of PI3K/Akt/mTOR pathway. Nonetheless, all cell lines demonstrated sensitivity to ridaforolimus within a clinically relevant dose-range (half-maximal inhibitory concentration (IC)=0.7-10 nM).
CONCLUSION
PTEN mutation is rare in sarcoma cell lines and constitutive activation of PI3K/Akt/mTOR is independent of PTEN status.
Topics: Cell Line, Tumor; Cell Proliferation; Humans; PTEN Phosphohydrolase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Sarcoma; TOR Serine-Threonine Kinases
PubMed: 27793898
DOI: 10.21873/anticanres.11160 -
BMC Cancer Oct 2016Mammalian target of rapamycin (mTOR) represents a key downstream intermediate for a myriad of oncogenic receptor tyrosine kinases. In the case of the insulin-like growth...
BACKGROUND
Mammalian target of rapamycin (mTOR) represents a key downstream intermediate for a myriad of oncogenic receptor tyrosine kinases. In the case of the insulin-like growth factor (IGF) pathway, the mTOR complex (mTORC1) mediates IGF-1 receptor (IGF-1R)-induced estrogen receptor alpha (ERα) phosphorylation/activation and leads to increased proliferation and growth in breast cancer cells. As a result, the prevalence of mTOR inhibitors combined with hormonal therapy has increased in recent years. Conversely, activated mTORC1 provides negative feedback regulation of IGF signaling via insulin receptor substrate (IRS)-1/2 serine phosphorylation and subsequent proteasomal degradation. Thus, the IGF pathway may provide escape (e.g. de novo or acquired resistance) from mTORC1 inhibitors. It is therefore plausible that combined inhibition of mTORC1 and IGF-1R for select subsets of ER-positive breast cancer patients presents as a viable therapeutic option.
METHODS
Using hormone-sensitive breast cancer cells stably transfected with the aromatase gene (MCF-7/AC-1), works presented herein describe the in vitro and in vivo antitumor efficacy of the following compounds: dalotuzumab (DALO; "MK-0646"; anti-IGF-1R antibody), ridaforolimus (RIDA; "MK-8669"; mTORC1 small molecule inhibitor) and letrozole ("LET", aromatase inhibitor).
RESULTS
With the exception of MK-0646, all single agent and combination treatment arms effectively inhibited xenograft tumor growth, albeit to varying degrees. Correlative tissue analyses revealed MK-0646 alone and in combination with LET induced insulin receptor alpha A (InsR-A) isoform upregulation (both mRNA and protein expression), thereby further supporting a triple therapy approach.
CONCLUSION
These data provide preclinical rationalization towards the combined triple therapy of LET plus MK-0646 plus MK-8669 as an efficacious anti-tumor strategy for ER-positive breast tumors.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Breast Neoplasms; Cell Proliferation; Drug Synergism; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Hormone-Dependent; Phosphorylation; Proto-Oncogene Proteins c-akt; RNA, Messenger; Real-Time Polymerase Chain Reaction; Receptor, IGF Type 1; Receptor, Insulin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 27765027
DOI: 10.1186/s12885-016-2847-3 -
Oncotarget Dec 2016Ridaforolimus is an investigational, potent, selective mTOR inhibitor. This study was conducted to determine the recommended phase 2 dose (RP2D), maximum tolerated dose,...
PURPOSE
Ridaforolimus is an investigational, potent, selective mTOR inhibitor. This study was conducted to determine the recommended phase 2 dose (RP2D), maximum tolerated dose, safety, pharmacokinetics, and antitumor activity of oral ridaforolimus in children with advanced solid tumors.
EXPERIMENTAL DESIGN
In this phase 1, multicenter, open-label study in children aged 6 to <18 years with advanced solid tumors, ridaforolimus was administered orally for 5 consecutive days/week in 28-day cycles until progression, unacceptable toxicity, or consent withdrawal. Dose started at 22 mg/m2 and increased to 28 mg/m2 and 33 mg/m2, followed by expansion at the RP2D.
RESULTS
Twenty patients were treated; 18 were evaluable for dose-limiting toxicities. One dose-limiting toxicity (grade 3 increased alanine aminotransferase) occurred in 1 patient at 33 mg/m2. Dose escalation concluded at 33 mg/m2; the maximum tolerated dose was not determined. The most common treatment-related adverse events (frequency ≥40%) were manageable grade 1-2 stomatitis, thrombocytopenia, hypertriglyceridemia, increased alanine aminotransferase, fatigue, hypercholesterolemia, anemia, and increased aspartate aminotransferase. Ridaforolimus exposure at 28 mg/m2 and 33 mg/m2 exceeded adult target levels. The RP2D for oral ridaforolimus in children was defined as 33 mg/m2. Four patients received at least 4 cycles; 2 with pineoblastoma and diffuse intrinsic pontine glioma had stable disease for 12 and 46 cycles, respectively.
CONCLUSIONS
Ridaforolimus is orally bioavailable and well tolerated in children with advanced solid tumors. The RP2D (33 mg/m2, 5 days/week) exceeds the adult RP2D. The favorable toxicity and pharmacokinetic profiles may allow for combination therapy, a promising therapeutic option in pediatric malignancies.
Topics: Administration, Oral; Adolescent; Adult; Antineoplastic Agents; Child; Combined Modality Therapy; Drug Dosage Calculations; Female; Humans; Male; Neoplasm Staging; Neoplasms; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases
PubMed: 27713169
DOI: 10.18632/oncotarget.12450 -
Journal of the National Cancer Institute Dec 2016Therapies cotargeting insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) have demonstrated remarkable, albeit short-lived, clinical...
BACKGROUND
Therapies cotargeting insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) have demonstrated remarkable, albeit short-lived, clinical responses in a subset of Ewing sarcoma (ES) patients. However, the mechanisms of resistance and applicable strategies for overcoming drug resistance to the IGF-1R/mTOR blockade are still undefined.
METHODS
To elucidate predominant mechanism(s) of acquired drug resistance while identifying synergistic drug combinations that improve clinical efficacy, we generated more than 18 ES cell lines resistant to IGF-1R- or mTOR-targeted therapy. Two small-molecule inhibitors of IGF-1R were chosen, NVP-ADW-742 (IGF-1R-selective) and OSI-906 (a dual IGF-1R/insulin receptor alpha [IR-α] inhibitor). Reverse-phase protein lysate arrays (RPPAs) revealed proteomic changes linked to IGF-1R/mTOR resistance, and selected proteins were validated in cell-based assays, xenografts, and within human clinical samples. All statistical tests were two-sided.
RESULTS
Novel mechanisms of resistance (MOR) emerged after dalotuzumab-, NVP-ADW-742-, and OSI-906-based targeting of IGF-1R. MOR to dalotuzumab included upregulation of IRS1, PI3K, and STAT3, as well as p38 MAPK, which was also induced by OSI-906. pEIF4E(Ser209), a key regulator of Cap-dependent translation, was induced in ridaforolimus-resistant ES cell lines. Unique drug combinations targeting IGF-1R and PI3K-alpha or Mnk and mTOR were synergistic in vivo and vitro (P < .001) as assessed respectively by Mantel-Cox and isobologram testing.
CONCLUSIONS
We discovered new druggable targets expressed by chemoresistant ES cells, xenografts, and relapsed human tumors. Joint suppression of these newfound targets, in concert with IGF-1R or mTOR blockade, should improve clinical outcomes.
Topics: Adenosine Triphosphatases; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cation Transport Proteins; Cell Line, Tumor; Copper-Transporting ATPases; Drug Resistance, Neoplasm; Drug Synergism; Humans; Imidazoles; Insulin Receptor Substrate Proteins; Male; Mice; Mice, SCID; Neoplasm Transplantation; Nucleocytoplasmic Transport Proteins; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Protein Array Analysis; Pyrazines; Pyrimidines; Pyrroles; Receptor, IGF Type 1; Receptors, Somatomedin; STAT3 Transcription Factor; Sarcoma, Ewing; Sirolimus; TOR Serine-Threonine Kinases; Up-Regulation; p38 Mitogen-Activated Protein Kinases
PubMed: 27576731
DOI: 10.1093/jnci/djw182 -
Expert Opinion on Drug Safety Aug 2016Despite advances in the treatment of metastatic breast cancer, the lack of response or relapse/progression during the course of therapy continue to present a challenge... (Review)
Review
INTRODUCTION
Despite advances in the treatment of metastatic breast cancer, the lack of response or relapse/progression during the course of therapy continue to present a challenge towards deeper understanding of dysregulated signaling pathways in breast cancer. Consequently, there is an unmet medical need for the development of new agents to overcome the resistance to therapy and improve the treatment outcome.
AREAS COVERED
In this review, the mechanism of action and the role of intracellular PI3K/AKT/mTOR signaling pathway inhibition in breast cancer patients are described. Everolimus has been approved in combination with exemestane for the treatment of hormone-receptor-positive advanced breast cancer after failure of nonsteroidal aromatase inhibitor therapy. The aim of this paper is to focus on the safety and efficacy of mTOR inhibitors in the treatment of breast cancer. Current strategies of major adverse event management and prevention are delineated.
EXPERT OPINION
Study results demonstrate clearly that the inhibition of the PI3K/AKT/mTOR pathway represents a promising approach to improve the efficacy of other targeted therapies in estrogen receptor-positive breast cancer patients with an acceptable safety profile. Although side effects are not uncommon, these are usually mild to moderate in severity and manageable with supportive care and dose adjustments.
Topics: Antineoplastic Agents; Breast Neoplasms; Drug Design; Drug Resistance, Neoplasm; Female; Humans; Molecular Targeted Therapy; Neoplasm Metastasis; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 27210004
DOI: 10.1080/14740338.2016.1192604