HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of Tanespimycin (17-AAG) Plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab

Abstract

Purpose: HSP90 is a chaperone protein required for the stability of a variety of client proteins. 17-Demethoxygeldanamycin (17-AAG) is a natural product that binds to HSP90 and inhibits its activity, thereby inducing the degradation of these clients. In preclinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer.Experimental Design: We enrolled patients with metastatic HER2 þ breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450 mg/m 2 intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Results: Thirty-one patients were enrolled with a median age of 53 years and a median Karnofsky performance status (KPS) of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea, and headache. The overall response rate was 22%, the clinical benefit rate [complete response þ partial response þ stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4-9), and the median overall survival was 17 months .Conclusions: This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic interaction and the activity of HSP90 inhibitors is clearly warranted.

High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer

“…For example, several potent, structurally diverse HSP90 inhibitors are currently in clinical trials. In breast cancer, the focus to date has been on HER2-positive disease, where addition of the firstgeneration HSP90 inhibitor tanespimycin (17-AAG) to trastuzumab therapy has demonstrated efficacy in patients who had previously progressed on trastuzumab alone (34)(35)(36).…”

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

“…A phase 2 clinical trial showed efficacy of an HSP90 inhibitor when combined with trastuzumab in the treatment of HER2-overexpressing metastatic breast cancer. 97 Nevertheless, the HSP90 approach has been in development for over a decade in patients with advanced breast cancer without clear evidence of clinical efficacy. A30, an RNA aptamer specific to the extracellular domain of HER3, is able to inhibit NRG-induced signaling.…”

“…(7) Inhibiting the heat shock protein 90 (HSP90), and consequently HER3 maturation and refolding, is another way to reduce HER3 stabilization. 97 (8) HER3 can be targeted by small RNA aptamer molecules, which bind with the extracellular domain of HER3 and inhibit downstream signaling. 98 (9) Using a peptidomimetic molecule binding HER2 and mimicking HER2-HER3s dimerization site is another way to prevent HER3 activation.…”

Medicine: Eyes on the target

“…Her team is evaluating one such drug, BYL719, and has also seen promising results from another approach to bolstering HER2-targeted treatment. Tumour cells rely on a molecule called heat-shock protein 90 (HSP90) to manage the production of HER2, and Modi and colleagues have found that chemical inhibition of HSP90 can stall HER2-dependent tumour growth 7 . "In our first phase 2 trial, we combined an HSP90 inhibitor with Herceptin and saw a nearly 25% response rate from just these two agents, without any chemo," she says.…”