Results of a Sarcoma Alliance for Research through Collaboration (SARC) phase II trial of dasatinib in previously treated, high-grade, advanced sarcoma.

Schuetze, Scott M.; Wathen, K.; Choy, Edwin; Samuels, Brian L.; Ganjoo, Kristen N.; Staddon, Arthur P.; Mehren, Margaret von; Chow, William; Trent, Jonathan C.; Baker, Laurence H.

doi:10.1200/jco.2010.28.15_suppl.10009

Cited by 28 publications

(11 citation statements)

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“…Sorafenib is a multikinase inhibitor that blocks receptor tyrosine kinases VEGFR and PDGF and the Raf serine/threonine kinases. Phase II clinical trials with receptor tyrosine kinase inhibitors Gleevec (13) and dasatinib have also been unsuccessful (14). It is probable that the heterogeneity of MPNSTs is an underlying cause for the lack of success in these clinical trials.…”

Section: Introductionmentioning

confidence: 99%

STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

Rad

Dodd

Thomas

et al. 2015

Molecular Cancer Research

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Therapeutic options are limited for neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNST) and clinical trials using drug agents have so far been unsuccessful. This lack of clinical success is likely attributed to high levels of intratumoral molecular heterogeneity and variations in signal transduction within MPNSTs. To better explore the variance of malignant signaling properties within heterogeneous MPNSTs, four MPNST cell lines (ST8814, S462, S1844.1, and S1507.2) were used. The data demonstrate that small-molecule inhibition of the MET proto-oncogene and mTOR had variable outcome when preventing wound healing, cell migration, and invasion, with the S462 cells being highly resistant to both. Of interest, targeted inhibition of the STAT3 transcription factor suppressed wound healing, cell migration, invasion, and tumor formation in all four MPNST lines, which demonstrates that unlike MET and mTOR, STAT3 functions as a common driver of tumorigenesis in NF1-MPNSTs. Of clinical importance, STAT3 knockdown was sufficient to block the expression of hypoxiainducible factor (HIF)1a, HIF2a, and VEGF-A in all four MPNST lines. Finally, the data demonstrate that wound healing, cell migration, invasion, and tumor formation through STAT3 are highly dependent on HIF signaling, where knockdown of HIF1a ablated these oncogenic facets of STAT3.Implications: This research reveals that aberrant STAT3 and HIF1a activity drives tumor progression in MPNSTs, indicating that inhibition of the STAT3/HIF1a/VEGF-A signaling axis is a viable treatment strategy.

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Section: Introductionmentioning

confidence: 99%

STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

Rad

Dodd

Thomas

et al. 2015

Molecular Cancer Research

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“…Dasatinib is an oral inhibitor of the SRC family of kinases, PDGFR, VEGF-R2, focal adhesion kinase (FAK), and human epidermal receptor-1/epidermal growth factor receptor (HER-1/EGFR). Dasatinib yielded ORR or SD in 8/42 (19%) undifferentiated pleomorphic sarcoma, 6/47 (12.8%) leiomyosarcoma, and 5/45 (11.1%) osteosarcoma, suggesting that its clinical benefit is STS-subtype specific [104].…”

Section: Targeted Therapiesmentioning

confidence: 94%

“…To circumvent the small number of STS patients, several studies have successfully implemented the Bayesian Hierarchical Statistical Model, useful for studying rare and heterogeneous diseases [94,104]. In addition, continued critical evaluation of clinical trial primary end points and evaluation methods will enhance and positively impact our efforts [127•, 128•, 129•].…”

Section: The Future and Conclusionmentioning

confidence: 99%

Systematic Therapy for Unresectable or Metastatic Soft-Tissue Sarcomas: Past, Present, and Future

Morgan

Cranmer

2011

Curr Oncol Rep

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Unresectable or metastatic disease occurs in 40% to 60% of soft-tissue sarcoma (STS) patients and portends a poor prognosis. For decades, doxorubicin has formed the backbone of systemic treatment, with response rates of approximately 26%. Patients progressing following first-line therapy were left with few proven options. No other cytotoxic chemotherapy agent or combination has demonstrated superiority to doxorubicin. Advances in targeted therapy of STS have been hindered by STS heterogeneity and poorly understood disease biology. Despite challenges, progress has been made in specific STS subtypes. Here, we highlight the challenges, progress, and lessons learned from STS trials published in the last 20 to 25 years.

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“…Preclinical studies revealed that inhibition of PDGFR effectively suppressed MPNST cell invasion and cell growth [32,44]. However, the monotherapeutic use of multikinase inhibitors with anti-PDGFR activity, such as imatinib mesylate, which blocks PDGFR, VEGFR, and c-Kit [45], the dual VEGFR/PDGFR inhibitor sorafenib [46], and dasatinib, which targets PDGFR and c-Kit in addition to BCR-ABL and the Src family [47] did not show a meaningful treatment response in phase II trials when tested in patients with refractory MPNSTs. The failure of RTK pathway inhibitors following the strong molecular evidence for RTK pathway targeting has been disappointing, especially when considering the treatment successes in other malignancies.…”

Section: /Tp53mentioning

confidence: 99%

Cancer of the Peripheral Nerve in Neurofibromatosis Type 1

2017

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The RASopathy neurofibromatosis 1 is an autosomal dominant hereditary cancer syndrome that represents a major risk for the development of malignancies, particularly malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are unique sarcomas that originate from the peripheral nerve and represent the only primary cancer of the peripheral nervous system. To date, surgery is the only treatment modality proven to have survival benefit for MPNSTs and even when maximal surgery is feasible, these tumors are rarely curable, despite the use of chemotherapy and radiation. In this review, we discuss the current state-of-the-art treatments for MPNSTs, latest therapeutic developments, and critical aspects of the underlying molecular and pathophysiology that appear promising for therapeutic developments in the future. In particular, we discuss the specific elements of cancer in the peripheral nerve and how that may impel development of unique therapies for this form of sarcoma.

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Results of a Sarcoma Alliance for Research through Collaboration (SARC) phase II trial of dasatinib in previously treated, high-grade, advanced sarcoma.

Cited by 28 publications

References 0 publications

STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

Systematic Therapy for Unresectable or Metastatic Soft-Tissue Sarcomas: Past, Present, and Future

Cancer of the Peripheral Nerve in Neurofibromatosis Type 1

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