Role of Targeted Therapy in Soft Tissue Sarcoma Treatment

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Role of NGS in suggesting treatment for STS

NGS of multiple genes can be done to identify molecular abnormalities in the tumor cells of patients with refractory disease. The identified molecular abnormalities may potentially match with several targeted therapies that are being tested in clinical trials or are available/approved for treatment of other cancer types.

Thus, NGS can help in the identification of potential clinical trial candidates. This approach can also be helpful in providing an alternative treatment to patients who are not responding to standard treatment or in the discovery of new treatment options for other such patients.

A most recent example of this application is the approval of larotrectinib for the treatment of pediatric and adult patients with STS or other tumors who have gene fusions involving one of the neurotrophic tropomyosin receptor kinase (NTRK) genes.

Role of Tyrosine Kinase Inhibitors (TKIs) in STS

Sorafenib

Sorafenib is a kinase inhibitor that is active against a variety of kinases including KIT, VEGFR-1–3, and PGDFR beta. It has shown clinical benefit for the treatment of patients with unresectable, KIT-positive GISTs who have received prior treatment with imatinib and sunitinib. It is also used in patients with solitary fibrous tumor, advanced epithelioid hemangioendothelioma, desmoid tumors (aggressive fibromatosis), angiosarcoma, and solitary fibrous tumor (Hemangiopericytoma).

Side effects of the drug include diarrhea, fatigue, infection, alopecia, hand-foot skin reaction, rash, weight loss, decreased appetite, nausea, abdominal pain, high blood pressure, and bleeding problems.

Pazopanib

Pazopanib is a multitargeted TKI that inhibit several kinases including VEGFR-1–3, PDGFR alpha and beta, KIT and others. It has been approved for the treatment of advanced soft tissue sarcomas other than adipocytic tumors and GISTs that have not responded to chemotherapy.

Pazopanib can cause side-effects like fatigue, nausea, diarrhea, decreased appetite, high blood pressure, headaches, changes in hair color, low blood cell counts, and liver problems.

Nilotinib

Some clinical studies have reported that nilotinib can confer clinical benefit in patients with unresectable, KIT-positive GIST who have received imatinib and sunitinib and progressed on these drugs, especially with KIT exon 17 mutations and not with KIT exon 9 mutation.

Dasatinib

Dasatinib is another kinase inhibitor that has demonstrated activity against PDGFRA D842V mutation that is commonly involved in the development of resistance to imatinib treatment. Thus, it could be a potentially effective treatment option for patients with imatinib-resistant GIST.

Role of mTOR Inhibitors in STS Treatment

Perivascular epithelioid cell tumors (PEComas) are mostly benign but can be malignant or aggressive, such as in the case of advanced-sage or recurrent lymphangioleiomyomatosis or angiomyolipomas. In most cases, PEComa tumors show dysregulated mammalian target of rapamycin (mTOR) signaling due to a mutation in the TSC1 or TSC2 genes leading to the tumor development and progression.

The mutation in the indicated genes may be inherited or sporadic. Targeted drugs directed towards mTOR, for example, sirolimus, temsirolimus, and everolimus have shown benefit in the treatment of advanced-stage PEComas. Sirolimus has been approved by US FDA for treatment of patients with pulmonary lymphangioleiomyomatosis.

Role of Monoclonal Antibodies in STS Treatment

Following are the 2 monoclonal antibodies which are currently recommended for the treatment of STSs:

Olaratumab

Olaratumab is a novel monoclonal antibody that binds to and inhibits PDGFR alpha. The activation of PDGFR alpha is thought to drive tumorigenesis and disease progression in STSs. Olaratumab, in combination with doxorubicin (a chemotherapeutic drug), has been approved for the treatment of patients with untreated, unresectable, or metastatic STS. Interestingly, the reported clinical benefit was consistent among all patients including those with the presence or absence of PDGFR alpha expression.

Side effects of combined treatment (olaratumab + doxorubicin) include infusion reactions, fatigue, nausea, musculoskeletal pain, hair loss, vomiting, diarrhea, decreased appetite, abdominal pain, neuropathy, and headache.

Bevacizumab

Bevacizumab is a monoclonal antibody that binds to vascular endothelial growth factor (VEGF) and inhibits its interaction with VEGFR. The drug has shown clinical benefit as single agent treatment for patients with highly vascular tumors, such as angiosarcoma and solitary fibrous tumor (hemangiopericytoma), or in combination with temozolomide (a chemotherapeutic drug) in patients with malignant SFT.

In other sections, we have discussed about the risk factorssymptomsinvestigationsstaging and treatment and targeted therapy for various STS types.

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