Sirolimus plus gemcitabine: a new therapeutic combination for resistant sarcomas?

Martín-Liberal, Juan; Tirado, Óscar M.; Muro, Xavier García del

doi:10.1586/14737140.2015.1003045

Cited by 5 publications

(2 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…BYL719, a novel α-specific PI3K inhibitor, combined with mafosfamide and ifosamide demonstrated a striking synergistic inhibition effect in osteosarcoma by inducing apoptosis 99 . Sirolimus, which targets the mTOR pathway by directly binding to mTORC1, combined with gemcitabine enhanced antitumor growth activity in leiomyosarcoma compared with treatment by the individual single-agent drugs in vitro and in vivo 100, 101 . Moreover, the same group conducted a Phase I study that demonstrated favorable results using the combination treatment in patients with advanced solid tumors, including chondrosarcoma.…”

Section: Targeting Serine/threonine Protein Kinases To Reverse Mdr Inmentioning

confidence: 99%

Targeting protein kinases to reverse multidrug resistance in sarcoma

Chen

Shen

Choy

et al. 2016

Cancer Treatment Reviews

View full text Add to dashboard Cite

Sarcomas are a group of cancers that arise from transformed cells of mesenchymal origin. They can be classified into over 50 subtypes, accounting for approximately 1% of adult and 15% of pediatric cancers. Wide surgical resection, radiotherapy, and chemotherapy are the most common treatments for the majority of sarcomas. Among these therapies, chemotherapy can palliate symptoms and prolong life for some sarcoma patients. However, sarcoma cells can have intrinsic or acquired resistance after treatment with chemotherapeutics drugs, leading to the development of multidrug resistance (MDR). MDR attenuates the efficacy of anticancer drugs and results in treatment failure for sarcomas. Therefore, overcoming MDR is an unmet need for sarcoma therapy. Certain protein kinases demonstrate aberrant expression and/or activity in sarcoma cells, which have been found to be involved in the regulation of sarcoma cell progression, such as cell cycle, apoptosis, and survival. Inhibiting these protein kinases may not only decrease the proliferation and growth of sarcoma cells, but also reverse their resistance to chemotherapeutic drugs to subsequently reduce the doses of anticancer drugs and decrease drug side-effects. The discovery of novel strategies targeting protein kinases opens a door to a new area of sarcoma research and provides insight into the mechanisms of MDR in chemotherapy. This review will focus on the recent studies in targeting protein kinase to reverse chemotherapeutic drug resistance in sarcoma.

show abstract

Section: Targeting Serine/threonine Protein Kinases To Reverse Mdr Inmentioning

confidence: 99%

Targeting protein kinases to reverse multidrug resistance in sarcoma

Chen

Shen

Choy

et al. 2016

Cancer Treatment Reviews

View full text Add to dashboard Cite

show abstract

“…Mechanistically, gemcitabine has shown to induce hyperactivation of the AKT/PI3K/mTOR pathway which is targeted and reversed by mTOR inhibitors ( 14 , 18 , 20 ). Clinically, the combination of gemcitabine with mTOR inhibitors has shown promising activity in prospective trials in osteosarcoma ( 23 ), in advanced soft-tissue sarcomas ( 24 , 25 ), and other solid tumors ( 14 , 26 ), without prior molecular screening for TSC mutations.…”

Section: Discussionmentioning

confidence: 99%

Case report: Responses to the combination of gemcitabine with sirolimus in two patients with TSC-mutated sarcomas

Nassif

Joseph²,

Lazcano³

et al. 2023

Front. Oncol.

View full text Add to dashboard Cite

TSC-mutated sarcomas are rare molecular and histologic types of sarcoma. Due to the presence of their specific oncogenic driver mutation, these sarcomas are particularly sensitive to mTOR inhibitors. Recently, nab-sirolimus, an albumin-bound mTOR inhibitor, was approved by the Food and Drug Administration (FDA) for PEComas, which harbor a TSC mutation, and this drug remains the only FDA-approved systemic treatment for these tumors. We report on two cases of patients with TSC-mutated sarcomas who experienced significant responses to the combination of gemcitabine and sirolimus, after progression on prior gemcitabine-based chemotherapy and single agent mTOR inhibition with nab-sirolimus. Preclinical and clinical data support rationale for a synergistic effect of the combination. This combination may represent a valid therapeutic option after failure of nab-sirolimus in these patients, with no standard-of-care treatment options.

show abstract