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
TL;DR: This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors and has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously 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 + 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 + partial response + stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4–9), and the median overall survival was 17 months (95% CI: 16–28). 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. Clin Cancer Res; 17(15); 5132–9. ©2011 AACR .
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TL;DR: Induced protein degradation has the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.
Abstract: Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function, and this approach typically precludes targeting proteins that lack such amenable sites. Furthermore, high systemic drug exposures may be needed to maintain sufficient target inhibition in vivo, increasing the risk of undesirable off-target effects. Induced protein degradation is an alternative approach that is event-driven: upon drug binding, the target protein is tagged for elimination. Emerging technologies based on proteolysis-targeting chimaeras (PROTACs) that exploit cellular quality control machinery to selectively degrade target proteins are attracting considerable attention in the pharmaceutical industry owing to the advantages they could offer over traditional small-molecule strategies. These advantages include the potential to reduce systemic drug exposure, the ability to counteract increased target protein expression that often accompanies inhibition of protein function and the potential ability to target proteins that are not currently therapeutically tractable, such as transcription factors, scaffolding and regulatory proteins.
854 citations
TL;DR: Success will likely lie in treating cancers that are addicted to particular driver oncogene products that are sensitive Hsp90 clients, as well as malignancies in which buffering of proteotoxic stress is critical for survival.
Abstract: Heat shock protein (Hsp) 90 is an ATP-dependent molecular chaperone exploited by malignant cells to support activated oncoproteins, including many cancer-associated kinases and transcription factors, and is essential for oncogenic transformation. Originally viewed with skepticism, Hsp90 inhibitors are now actively pursued by the pharmaceutical industry, with 17 agents having entered clinical trials. Hsp90’s druggability was established using the natural products geldanamycin and radicicol which mimic the unusual ATP structure adopted in the chaperone’s N-terminal nucleotide-binding pocket and cause potent and selective blockade of ATP binding/hydrolysis, inhibit chaperone function, deplete oncogenic clients, and demonstrate antitumor activity. Preclinical data with these natural products have heightened interest in Hsp90 as a drug target, and 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) has demonstrated clinical activity (as defined by RECIST criteria) in HER2+ breast cancer. Many optimized synthetic small molecule Hsp90 inhibitors from diverse chemotypes are now in clinical trials. We review the discovery and development of Hsp90 inhibitors and assess their future potential. There has been significant learning from experience in both the basic biology and the translational drug development around Hsp90, enhanced by the use of Hsp90 inhibitors as chemical probes. Success will likely lie in treating cancers addicted to particular driver oncogene products, such as HER2, ALK, EGFR and BRAF, that are sensitive Hsp90 clients, as well as in malignancies, especially multiple myeloma, where buffering of proteotoxic stress is critical for survival. We discuss approaches to enhancing the effectiveness of Hsp90 inhibitors and highlight new chaperone and stress response pathway targets, including HSF1 and Hsp70.
830 citations
TL;DR: This Timeline article focuses on the ERBB network of receptor tyrosine kinases (RTKs), which exemplifies how a constant dialogue between basic research and medical oncology can translate into both a sustained pipeline of novel drugs and ways to overcome acquired treatment resistance in patients.
Abstract: Although it is broadly agreed that the improved treatment of patients with cancer will depend on a deeper molecular understanding of the underlying pathogenesis, only a few examples are already available. This Timeline article focuses on the ERBB (also known as HER) network of receptor tyrosine kinases (RTKs), which exemplifies how a constant dialogue between basic research and medical oncology can translate into both a sustained pipeline of novel drugs and ways to overcome acquired treatment resistance in patients. We track the key early discoveries that linked this RTK family to oncogenesis, the course of pioneering clinical research and their merger into a systems-biology framework that is likely to inspire further generations of effective therapeutic strategies.
775 citations
TL;DR: This review will compare advantages and disadvantages of multitarget versus combination therapies, discuss potential drug promiscuity arising from off-target effects, comment on drug repurposing, and introduce approaches to the computational design of multi-target drugs.
Abstract: At present, the legendary magic bullet, i.e., a drug with high potency and selectivity toward a specific biological target, shares the spotlight with an emerging and alternative polypharmacology approach. Polypharmacology suggests that more effective drugs can be developed by specifically modulating multiple targets. It is generally thought that complex diseases such as cancer and central nervous system diseases may require complex therapeutic approaches. In this respect, a drug that "hits" multiple sensitive nodes belonging to a network of interacting targets offers the potential for higher efficacy and may limit drawbacks generally arising from the use of a single-target drug or a combination of multiple drugs. In this review, we will compare advantages and disadvantages of multitarget versus combination therapies, discuss potential drug promiscuity arising from off-target effects, comment on drug repurposing, and introduce approaches to the computational design of multitarget drugs.
740 citations
TL;DR: This review summarizes the current status of both first and second generation HSP90 inhibitors based on their chemical classification and stage of clinical development and discusses the pharmacodynamic assays currently implemented in clinic as well as other novel strategies aimed at enhancing the effectiveness of Hsp90 inhibitors.
411 citations
Cites background from "HSP90 Inhibition Is Effective in Br..."
...In order to obtain a more precise estimate of activity, the phase II trial enrolled 31 patients with HER2+ metastatic breast cancer who were previously refractory to trastuzumab therapy [29]....
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References
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TL;DR: A model by which a combined assessment of all existing lesions, characterized by target lesions and nontarget lesions, is used to extrapolate an overall response to treatment is proposed, which is largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines.
Abstract: Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.
14,926 citations
TL;DR: The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression, a higher rate of objective response, a longer duration of response, and a lower rate of death at 1 year.
Abstract: Background The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. Methods We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide with (143 women) or without trastuzumab (138 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). Results The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 ...
10,532 citations
"HSP90 Inhibition Is Effective in Br..." refers background in this paper
...survival and extends time to progression when combined with first-line chemotherapy for metastatic disease (1), and increases survival in the adjuvant setting (3–5)....
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...Breast cancers with HER2 amplification form a distinct class that is dependent on this receptor and sensitive to its inhibition (1)....
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TL;DR: Tastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer.
Abstract: Background We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer. Methods The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclit...
5,200 citations
McGill University1, Ludwig Maximilian University of Munich2, The Royal Marsden NHS Foundation Trust3, Autonomous University of Barcelona4, Geelong Hospital5, University of Marburg6, University of Edinburgh7, Pontifícia Universidade Católica do Rio Grande do Sul8, National Taiwan University9, University of Copenhagen10, Tel Aviv Sourasky Medical Center11, Russian Academy12, University of Düsseldorf13, University of Hamburg14, University of British Columbia15, University of Bern16, Hoffmann-La Roche17, Université libre de Bruxelles18, Harvard University19
TL;DR: One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer.
Abstract: background Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2. We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy. methods This international, multicenter, randomized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. results Data were available for 1694 women randomly assigned to two years of treatment with trastuzumab, 1694 women assigned to one year of trastuzumab, and 1693 women assigned to observation. We report here the results only of treatment with trastuzumab for one year or observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P<0.0001 by the log-rank test, crossing the interim analysis boundary), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab. conclusions One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer. (clinicaltrials.gov number, NCT 00045032.)
4,815 citations
TL;DR: Lapatinib plus capecitabine is superior to cape citabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab.
Abstract: A b s t r ac t The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events. Conclusions Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2- positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. (ClinicalTrials.gov number, NCT00078572.)
3,149 citations
"HSP90 Inhibition Is Effective in Br..." refers background in this paper
...The significant antitumor activity of lapatinib (6), a HER2 tyrosine kinase inhibitor, in these patients, along with the activity of...
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