Stage 2 Combination Testing of Rapamycin with Cytotoxic Agents by the Pediatric Preclinical Testing Program

Houghton, Peter J.; Morton, Christopher L.; Görlick, Richard; Lock, Richard B.; Carol, Hernán; Reynolds, C. Patrick; Kang, Min H.; Maris, John M.; Keir, Stephen T.; Kolb, E. Anders; Wu, Jianrong; Wozniak, Amy; Billups, Catherine A.; Rubinstein, Larry; Smith, Malcolm A.

doi:10.1158/1535-7163.mct-09-0952

Cited by 91 publications

(89 citation statements)

References 32 publications

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“…In other studies, mTOR inhibition was also shown to sensitize cancer cells to chemotherapy, including pediatric sarcoma models. 24,25 Moreover, the mTOR inhibitor everolimus dramatically enhanced cisplatin-induced apoptosis in wildtype p53, but not mutant p53, tumor cells. 26 Both OS-1 and OS-33 models are p53-wildtype, as is the majority (62%) of clinical osteosarcoma samples.…”

Section: Discussionmentioning

confidence: 99%

“…Additive efficacy was reported in one out of two osteosarcoma models, but excessive toxicity was observed in these models as well. 24 Rapamycin combined with cisplatin also resulted in excessive toxicity. However, at lower doses of cisplatin, rapamycin potentiated cisplatin activity.…”

Section: Discussionmentioning

confidence: 99%

“…However, at lower doses of cisplatin, rapamycin potentiated cisplatin activity. 24 To avoid toxicity problems in our in vivo therapy experiments and eventually in the clinic, we used relatively low and clinically applicable doses of temsirolimus and cisplatin, and this combination turned out to be well tolerated in mice. Even at these relatively low doses, significant growth inhibition was demonstrated in both monotherapy groups (with the exception of cisplatin in OS-1 tumors), and superior efficacy was demonstrated with the combination in both osteosarcoma models.…”

Section: Discussionmentioning

confidence: 99%

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Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models

et al. 2014

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Mammalian target of rapamycin (mTOR) is a new promising oncological target. However, most clinical studies reported only modest antitumor activity during mTOR-targeted monotherapies, including studies in osteosarcomas, emphasizing a need for improvement. We hypothesized that the combination with rationally selected other therapeutic agents may improve response. In this study, we examined the efficacy of the mTOR inhibitor temsirolimus combined with cisplatin or bevacizumab on the growth of human osteosarcoma xenografts (OS-33 and OS-1) in vivo, incorporating functional imaging techniques and microscopic analyses to unravel mechanisms of response. In both OS-33 and OS-1 models, the activity of temsirolimus was significantly enhanced by the addition of cisplatin (TC) or bevacizumab (TB). Extensive immunohistochemical analysis demonstrated apparent effects on tumor architecture, vasculature, apoptosis and the mTOR-pathway with combined treatments. Osteosarcoma is the most commonly diagnosed primary malignant tumor of the bone mainly affecting children and adolescents. 1 Current standard treatment regimens consist of surgery and polychemotherapy. Unfortunately, despite multimodal treatment the final outcome has not improved significantly during the last decade and severe side effects of intensive chemotherapy treatment schedules are observed frequently. On top of that, research on targeted treatments in osteosarcomas lags behind. This underscores the absolute need for novel, targeted therapies to treat these often young patients.Blocking of mammalian target of rapamycin (mTOR) signaling emerged as a promising approach to target osteosarcomas. mTOR, also known as sirolimus effector protein, is an intracellular serine/threonine kinase involved in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascade and signals downstream of several receptor tyrosine kinases (RTKs), including but not limited to the insulin-like growth factor 1

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models

et al. 2014

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“…Our group, and others, have demonstrated that rapalogs have an additive or synergistic effect when combined with many agents in vitro, including methotrexate, corticosteroids, doxorubicin, etoposide, and asparaginase. [136,[144][145][146] An added benefit was not found when rapalogs were combined with vincristine in vitro; however, the combination was found to be more effective than either drug alone in vivo. [136,139,146] Rapalogs have been studied in vivo in combination with methotrexate and corticosteroids.…”

Section: Acute Lymphoblastic Leukemiamentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen.Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual-and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignanc...

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“…Rapamycin (RAPA) is the special inhibitor of mTOR, which has demonstrated anti-tumor effects in a variety of malignancies in preclinical and clinical studies. In addition to being used as a monotherapy, RAPA and its analogs have been shown to enhance the efficacy of a number of cytotoxic chemotherapeutic agents in various types of cancer (8)(9)(10)(11). Studies have shown that the anti-tumor mechanism of RAPA includes both apoptosis and autophagy, and its role in the fate of cancer cells remains controversial (12).…”

Section: Introductionmentioning

confidence: 99%

Rapamycin synergizes with low-dose oxaliplatin in the HCT116 colon cancer cell line by inducing enhanced apoptosis

et al. 2011

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Abstract. The present study aimed to examine the combined effects of oxaliplatin (L-OHP) and rapamycin (RAPA) in the HCT116 colon cancer cell line. The growth inhibitory effect was evaluated by MTT assay as a monotherapy or combination therapy. IC 50 values were determined using CalcuSyn 2.0 software. To determine the interaction of the drugs, the combination index (CI) was calculated using the Chou-Talalay method. Apoptosis was investigated using flow cytometry and Western blotting. Acridine orange staining was employed to observe morphological changes. The results showed the IC 50 values of L-OHP and RAPA to be 8.35±0.78 µM (r=0.99) and 223.44±38.10 nM (r=0.94), respectively. CI was ≤1 when L-OHP was used at doses ranging from 1 to 5 µM plus RAPA at a dose of 10 nM, suggesting synergistic or additive effects. CI was ≥1 when 100 nM RAPA was used in combination with low-dose L-OHP, showing additive to antagonistic effects. The combination of L-OHP (1 µM) and RAPA (10 nM) induced 19.76% Annexin V-positive cells, which was found to be higher than L-OHP (11.45%, p<0.01) or RAPA (6.89%, p<0.01) alone. The cleaved PARP protein expression levels were highest after 48 h of combination treatment. Acridine orange staining showed typical bright red Acidic vesicular organelles in the RAPA group, whereas the green condensed chromatin in the apoptotic bodies was found in both the L-OHP and combination groups. In conclusion, at a cytostatic concentration, RAPA was found to potentiate the anti-tumor effects of low-dose L-OHP in the HCT116 colon cancer cell by inducing enhanced apoptosis. IntroductionColorectal cancer (CRC) is the second most prevalent cancer and the third leading cause of cancer deaths worldwide (1). Oxaliplatin (L-OHP)-based chemotherapeutic regimens have proven to be effective in the prevention and treatment of tumor recurrence and metastasis in CRC. However, drug toxicity remains to be clarified in the clinic (2). Efforts have focused on incorporating cytotoxic and molecularly targeted agents into chemotherapy regimens to decrease toxicity and increase efficacy (3-5).The mammalian target of rapamycin (mTOR), an intracellular protein with a central role in the synthesis of key cellular proteins, has emerged as a significant target for anticancer therapy in various types of tumor. Phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway has been reported to be constitutively overexpressed in malignant tumors including CRC (6-7). Rapamycin (RAPA) is the special inhibitor of mTOR, which has demonstrated anti-tumor effects in a variety of malignancies in preclinical and clinical studies. In addition to being used as a monotherapy, RAPA and its analogs have been shown to enhance the efficacy of a number of cytotoxic chemotherapeutic agents in various types of cancer (8-11). Studies have shown that the anti-tumor mechanism of RAPA includes both apoptosis and autophagy, and its role in the fate of cancer cells remains controversial (12). The interaction between RAPA and L-OHP has yet to be clarified as the role of apo...

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Stage 2 Combination Testing of Rapamycin with Cytotoxic Agents by the Pediatric Preclinical Testing Program

Cited by 91 publications

References 32 publications

Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models

Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

Rapamycin synergizes with low-dose oxaliplatin in the HCT116 colon cancer cell line by inducing enhanced apoptosis

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