Combination therapy with Olaratumab/doxorubicin in advanced or metastatic soft tissue sarcoma -a single-Centre experience

Brandes, Franziska; Baur, Alexander; Pfitzner, Berit Maria; Kaul, David; Rau, Daniel; Dörr, Anne; Schmiester, Maren; Koulaxouzidis, Georgios; Bullinger, Lars; Märdian, Sven; Flörcken, Anne

doi:10.1186/s12885-020-6551-y

Cited by 4 publications

(3 citation statements)

References 26 publications

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“…To our surprise, pazopanib and 602 did not interact, with the drug combination causing only approximately a twenty percent increase in killing over either agent individually. Prior to the approval of pazopanib, STS was treated with a variety of well-established cytotoxic chemotherapy regimens, including doxorubicin ( 11 , 12 ). In further preliminary studies 602 and doxorubicin interacted in an additive to greater than additive fashion to kill STS cells.…”

Section: Introductionmentioning

confidence: 99%

GZ17-6.02 and Doxorubicin Interact to Kill Sarcoma Cells via Autophagy and Death Receptor Signaling

et al. 2020

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GZ17-6.02 (602) is presently under phase I clinical evaluation (NCT03775525). We defined the mechanisms by which it interacted with a standard of care therapeutic doxorubicin to kill sarcoma cells. Doxorubicin and 602 interacted to rapidly activate ATM and c-MET, inactivate mTOR, AKT, and p70 S6K, enhance the expression of Beclin1 and reduce the levels of K-RAS and N-RAS. This was followed later by the drugs interacting to reduce expression of MCL-1, BCL-XL, and HDAC6. Knock down of ATM prevented the drugs alone or in combination inactivating mTOR or activating ULK1. Knock down of c-MET significantly enhanced [doxorubicin + 602] lethality. Knock down of ATM and to a greater extent ULK1, Beclin1, or ATG5 significantly reduced killing by 602 alone or when combined with doxorubicin. Expression of an activated mTOR mutant suppressed killing, autophagosome formation and prevented autophagic flux. In the absence of Beclin1, knock down of CD95, or FADD, or over-expression of c-FLIP-s or BCL-XL abolished tumor cell killing. We conclude that 602 and doxorubicin interact to increase autophagosome formation and autophagic flux as well as causing elevated death receptor signaling resulting in mitochondrial dysfunction and tumor cell death.

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Section: Introductionmentioning

confidence: 99%

GZ17-6.02 and Doxorubicin Interact to Kill Sarcoma Cells via Autophagy and Death Receptor Signaling

et al. 2020

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“…The median PFS in this group was 3.1 months and median OS was 4.6 months. 16 The low response rate was also observed in a retrospective analysis of 55 patients from different centers in Austria who received the Olaratumab and Doxorubicin combination. In this cohort, only 11.4% of the patients experienced some response, with a reported median PFS of 2.6 months of and a median OS of 11.4 months.…”

Section: Discussionmentioning

confidence: 75%

Olaratumab’s failure in soft tissue sarcoma

et al. 2021

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Soft tissue sarcomas remain one of the rarest malignancies with numerous subtypes that go undiagnosed. The PDGFRα antagonist Olaratumab (Lartruvo) was withdrawn from the market due to disappointing findings in the phase III studies. We share our experience with this medication in a tertiary care center in the Middle East and North Africa region. Monitor the effect of Olaratumab on sarcomas when it was used prior to its withdrawal, and compare our findings with the literature. We performed a retrospective analysis of adult patients with advanced-/metastatic soft tissue sarcomas treated with at least two cycles of Olaratumab at a tertiary care center in Lebanon during the period from January 1, 2017 to December 31, 2018. Fifteen patients were included in the study. The mean age was 49 with a range of 26–75 years. The median duration of the use of Olaratumab was 21.3 months with a range of 7.3–37 months. The average number of number of cycles received per patient was four. Five patients were deceased. Median PFS was 7.87 months (95% CI 5.28–10.45), and mean OS was 12.26 months (95% CI 8.47–16.05) Median OS was 9.8 months (95% CI 6.07–13.53). Olaratumab has been withdrawn from the market, and it is currently being investigated as part of the phase II ANNOUNCE 2 trial. Our experience from a tertiary care center shows results similar to those reported in the literature. The immunogenicity and heterogeneity of soft tissue sarcomas pose a challenge to the treatment of soft tissue sarcomas, but they also allow a wide array of possible management solutions.

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“…Trials combining standard cytotoxic therapy with targeted therapy have also been performed. Rriociclib, sorafenib, and olaratumab in combination with chemotherapy drugs did not show the expected improvement in treatment results [27,[141][142][143]. However, targeting neurotrophic tyrosine receptor kinases (NTRK) seems to be beneficial in patients with TRK-mutated solid tumors with an ORR of 34%; yet no specific results for MPNST have been posted [144].…”

Section: Targeted Treatment and Clinical Trialsmentioning

confidence: 99%

Malignant peripheral nerve sheath tumor — from genetics to multidisciplinary treatment

Czarnecka,

Chmiel,

Sobczuk

et al. 2024

Oncol Clin Pract

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Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma (STS); it originates from nervous tissue and typically develops in proximity to nerve trunks in the limbs and trunk. These tumors, constituting approximately 5% of soft tissue sarcomas, can either form spontaneously or arise from pre-existing neurofibromas. The majority (90%) of cases occur in individuals between the 2 nd and 5 th decades of life. The main risk factor for MPNST is von Recklinghausen disease (type 1 neurofibromatosis). The cornerstone of MPNST management involves radical surgical measures, specifically tumor excision within healthy tissue boundaries (wide local excision), which is complemented by adjuvant radiotherapy. In case of metastatic disease, palliative chemotherapy employing doxorubicin or a combination of doxorubicin and ifosfamide is utilized. Approximately 25-30% of patients experience clinical improvement after chemotherapy. Looking ahead, advancements in research on molecular biology may lead to the development of inhibitors demonstrating greater efficacy than traditional chemotherapy for MPNST patients. At present, ongoing clinical trials of the therapeutic management of MPNST encompass pembrolizumab, the combination of nivolumab with ipilimumab, pexydartinib (an inhibitor targeting KIT, CSF1R, and FLT3) in conjunction with sirolimus, sapanisertib (a TORC1/2 inhibitor), or LOXO-195 (an inhibitor of neurotrophic tyrosine kinase receptors NTRK type 1, 2, and 3).

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Combination therapy with Olaratumab/doxorubicin in advanced or metastatic soft tissue sarcoma -a single-Centre experience

Cited by 4 publications

References 26 publications

GZ17-6.02 and Doxorubicin Interact to Kill Sarcoma Cells via Autophagy and Death Receptor Signaling

GZ17-6.02 and Doxorubicin Interact to Kill Sarcoma Cells via Autophagy and Death Receptor Signaling

Olaratumab’s failure in soft tissue sarcoma

Malignant peripheral nerve sheath tumor — from genetics to multidisciplinary treatment

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