Olaratumab: A Novel Platelet-Derived Growth Factor Receptor α-Inhibitor for Advanced Soft Tissue Sarcoma

Andrick, Benjamin; Gandhi, Arpita

doi:10.1177/1060028017723935

Cited by 10 publications

(8 citation statements)

References 34 publications

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“…Given the association between PDGF over-activity and malignant tumors, different kinds of PDGF inhibitors have been developed. These inhibitors include the fully human IgG1 monoclonal antibody against PDGFRα named olaratumab ( 108 ), and multi-target TKIs such as cediranib, imatinib, and sorafenib ( Table 1 ).…”

Section: Which Rtk Is the Key Target?mentioning

confidence: 99%

Receptor Tyrosine Kinases in Osteosarcoma Treatment: Which Is the Key Target?

2020

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Recent clinical trials have shown several multi-target tyrosine kinase inhibitors (TKIs) to be effective in the treatment of osteosarcoma. However, these TKIs have a number of targets, and it is yet unclear which of these targets has a key role in osteosarcoma treatment. In this review, we first summarize the TKIs that were studied in clinical trials registered on ClinicalTrials.gov. Further, we compare and discuss the targets of these TKIs. We found that TKIs with promising therapeutic effect for osteosarcoma include apatinib, cabozantinib, lenvatinib, regorafenib, and sorafenib. The key targets for osteosarcoma treatment may include VEGFRs and RET. The receptor tyrosine kinases (RTKs) MET, IGF-1R, AXL, PDGFRs, KIT, and FGFRs might be relevant but unimportant targets for osteosarcoma treatment. Inhibition of one type of RTK for the treatment of osteosarcoma is not effective. It is necessary to inhibit several relevant RTKs simultaneously to achieve a breakthrough in osteosarcoma treatment. This review provides comprehensive information on TKI targets relevant in osteosarcoma treatment, and it will be useful for further research in this field.

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Section: Which Rtk Is the Key Target?mentioning

confidence: 99%

Receptor Tyrosine Kinases in Osteosarcoma Treatment: Which Is the Key Target?

2020

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“…Different studies quote different survival data based on treatment approach applied and a uniform consensus does not exist regarding survival rates. Important prognostic factors include tumour size and the presence or absence of metastasis at the time of diagnosis 23. In one study, patients with angiosarcoma showed better 5-year survival if the primary lesion was <5 cm.…”

Section: Discussionmentioning

confidence: 99%

Primary renal angiosarcoma: a diagnostic and therapeutic challenge

Lodhi

Inayat²,

Munir

et al. 2018

BMJ Case Reports

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Primary renal angiosarcoma is an exceedingly rare and aggressive neoplasm. Although it may occur in youth, this tumour is frequently reported in the sixth and seventh decades of life. The clinical presentation is frequently varied. Pathogenesis remains largely unknown and it has overlapping features with other tumours of the kidney. Current treatment options include variable combinations of surgery, chemotherapy and radiotherapy. Reports regarding the disease prognosis and natural history are limited. In this article, we chronicle the case of a patient with primary renal angiosarcoma presenting at an advanced stage as a widely metastasised tumour. Additionally, we undertake here a brief literature review highlighting the rarity and aggressiveness of this condition, its poor prognosis, and the lack of specific management guidelines.

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“…Controversy exists regarding the value of currently available treatments, such as chemotherapy, to reduce the rate of metastasis [6]. Prognosis for metastatic STS is poor, with overall survival of approximately 18 months [7] and estimated five-year survival of 16% [8].…”

Section: Introductionmentioning

confidence: 99%

“…Management of STS requires a multidisciplinary approach which can include surgery, chemotherapy, and radiation therapy (RT). For patients with low-risk disease and relatively low probability of metastatic spread, local resection (often in conjunction with RT) is largely efficacious as reflected in the high five-year survival rate of 83% [8]. In contrast, patients with high-risk disease generally have poorer survival, despite effective local control.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, patients with high-risk disease generally have poorer survival, despite effective local control. Doxorubicin has remained the cornerstone of chemotherapy regimens for advanced and metastatic STS both as monotherapy and in conjunction with other agents since 1975, the year in which its efficacy was first demonstrated [9], despite the heterogeneity across STS subtypes, presentations, and other patient characteristics [8]. Several other drugs have been combined with doxorubicin, including ifosfamide analogues like palifosfamide and evofosfamide and targeted agents such as bevacizumab and cixutumumab.…”

Section: Introductionmentioning

confidence: 99%

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Investigating a chimeric anti-mouse PDGFRα antibody as a radiosensitizer in primary mouse sarcomas

et al. 2019

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BackgroundOlaratumab (LY3012207/IMC-3G3/Lartruvo™) is a fully human monoclonal antibody specific for platelet-derived growth factor receptor alpha (PDGFRα). Phase Ib/II trial results of olaratumab plus doxorubicin in adult patients with advanced soft tissue sarcoma (STS) supported accelerated FDA approval of this regimen. Radiation therapy (RT) is frequently used for high-risk localized STS. However, olaratumab has not been tested with concurrent RT. Here, we evaluate the chimeric anti-mouse PDGFRα antibody 1E10Fc as a radiosensitizer in a primary mouse model of STS.MethodsPrimary STS were initiated in mice. When tumors reached 70 mm3, mice were allocated into treatment groups: 1) isotype, 2) 1E10Fc, 3) isotype + RT, 4) 1E10Fc + RT. 1E10Fc or isotype was given biweekly. RT (25 Gy delivered in 5 daily 5 Gy fractions) was initiated on Day 0 with first drug treatment. Tumors were measured 3× per week. Upon reaching 900 mm3, tumors and lungs were harvested. A two-way ANOVA was performed to compare tumor growth delay. Primary tumors were stained for CD31 and PDGFRα and lungs were assessed for micrometastases. A Chi-square test was performed to compare the development of micrometastases in the lungs after treatment with 1E10Fc or isotype.FindingsRT significantly delayed time to tumor quintupling compared to no RT (p < 0·0001) [two-way ANOVA], but no difference in tumor growth was seen between mice receiving isotype or 1E10Fc treatment regardless of concurrent RT. Lower microvessel density was observed in the 1E10Fc + RT group. Fewer mice treated with 1E10Fc had micrometastases, but this difference was not statistically significant (p < 0·09).Interpretation1E10Fc did not act as a radiosensitizer in this primary STS model.FundingThis study was funded by a research agreement from Eli Lilly and Company.

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Olaratumab: A Novel Platelet-Derived Growth Factor Receptor α-Inhibitor for Advanced Soft Tissue Sarcoma

Abstract: Olaratumab, in combination with doxorubicin, represents a novel treatment strategy for advanced soft tissue sarcoma and provides a significant survival advantage for this rare disease state with limited treatment options.

Cited by 10 publications

References 34 publications

Receptor Tyrosine Kinases in Osteosarcoma Treatment: Which Is the Key Target?

Receptor Tyrosine Kinases in Osteosarcoma Treatment: Which Is the Key Target?

Primary renal angiosarcoma: a diagnostic and therapeutic challenge

Investigating a chimeric anti-mouse PDGFRα antibody as a radiosensitizer in primary mouse sarcomas

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