Abstract
Purpose177Lu-DOTATATE targeting the somatostatin receptor (SSTR) is utilized for treatment of neuroendocrine tumors (NETs). Onalespib, a heat shock protein 90 (HSP90) inhibitor, has demonstrated radiosensitizing properties and may thus enhance the effect of 177Lu-DOTATATE. Consequently, the aim of this study was to assess the potential of Onalespib in combination with 177Lu-DOTATATE in vivo and to examine the toxicity profiles of the treatments.Methods177Lu-DOTATATE selectivity and distribution in NET xenografts were studied using biodistribution and autoradiography. Therapeutic effects of Onalespib in combination with 177Lu-DOTATATE were studied in NET xenografts. Histological analyses were used to assess molecular effects from treatment and to establish toxicity profiles.ResultsBiodistribution and autoradiography confirmed the SSTR-selective tumor uptake of 177Lu-DOTATATE, which was unaffected by Onalespib treatment. Immunohistochemistry verified molecular responses to Onalespib therapy in the tumors. While Onalespib and 177Lu-DOTATATE monotherapies resulted in a 10% and 33% delay in tumor doubling time compared with control, the combination treatment resulted in a 73% delayed tumor doubling time. Moreover, combination treatment increased complete remissions threefold from 177Lu-DOTATATE monotherapy, resulting in 29% complete remissions. In addition, histological analyses demonstrated radiation-induced glomerular injury in the 177Lu-DOTATATE monotherapy group. The damage was decreased tenfold in the combination group, potentially due to Onalespib-induced HSP70 upregulation in the kidneys.ConclusionTreatment with Onalespib potentiated 177Lu-DOTATATE therapy of NET xenografts with a favorable toxicity profile. Utilizing Onalespib’s radiosensitizing properties with 177Lu-DOTATATE may lead to better therapeutic results in the future and may reduce unwanted side effects in dose-limiting organs.
Highlights
Tumors that arise from the neuroendocrine system can occur throughout the body, but the most common sites of the primary disease are the gastrointestinal (GI) tract and the lungs [1]
We have recently demonstrated the potential of combining 177Lu-DOTATATE with Onalespib in vitro [30], and another heat shock protein 90 (HSP90) inhibitor was recently shown to reduce tumor growth when combined with external radiotherapy or 177Lu-DOTATATE in small intestine Neuroendocrine tumors (NETs) xenografts [16]
We hypothesized that HSP90 inhibitor Onalespib could potentiate 177Lu-DOTATATE treatment of neuroendocrine tumors in vivo
Summary
Tumors that arise from the neuroendocrine system can occur throughout the body, but the most common sites of the primary disease are the gastrointestinal (GI) tract and the lungs [1]. Neuroendocrine tumors (NETs) consist of around 2% of all cancer cases and there is a wide range in malignancy within this disease group [1, 2]. While early-stage disease is regularly surgically resected, patients diagnosed at a later stage frequently present with metastases. For this patient group, curative surgery is rarely an option [1, 2]. Peptide receptor radionuclide therapy (PRRT) targeting the somatostatin receptors (SSTRs) has revolutionized the treatment of metastatic or inoperable NETs [3].
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