Glembatumumab vedotin for patients with metastatic, gpNMB overexpressing, triple-negative breast cancer (“METRIC”): a randomized multicenter study

Vahdat, Linda T.; Schmid, Peter; Forero‐Torres, Andres; Blackwell, Kimberly; Telli, Melinda L.; Melisko, Michelle; Möbus, V.; Cortés, Javier; Montero, Alberto J.; Ma, Cynthia; Nanda, Rita; Wright, Gail S.; He, Yunlong; Hawthorne, Thomas; Halim, Abdel; Turner, Christopher D.; Yardley, Denise A.

doi:10.1038/s41523-021-00244-6

Cited by 36 publications

(28 citation statements)

References 34 publications

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“…Glembatumumab vedotin is currently being tested in clinical trials as a GPNMB-targeted therapy and is being tested for clinical use in breast cancer, malignant melanoma, and recurrent osteosarcoma (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

GPNMB-Positive Cells in Head and Neck Squamous Cell Carcinoma—Their Roles in Cancer Stemness, Therapy Resistance, and Metastasis

Kawasaki¹,

Suzuki²,

Suzuki³

et al. 2022

Pathol. Oncol. Res.

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Objective: Despite the use of surgical and chemoradiation therapies, head and neck squamous cell carcinoma (HNSCC) still has a poor prognosis. Immune checkpoint inhibitors have been shown to prolong life expectancy but have limited efficacy. Glycoprotein nonmetastatic melanoma protein B (GPNMB) has received significant attention in breast cancer treatment, in which it has been associated with cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT); however, the function of GPNMB in HNSCC is completely unknown. This study aimed to clarify the characteristics of GPNMB-positive cells in vitro and their association with the prognosis by immunostaining clinical specimens.Methods: We examined the sphere formation, invasion, and migration ability of GPNMB-positive cells in four HNSCC cell lines in vitro. We also immunostained biopsy specimens with GPNMB from 174 patients with HNSCC diagnosed, treated, and followed-up in our institution to evaluate overall survival and progression-free survival.Results: GPNMB-positive cells showed enhanced sphere formation, invasion, and migration, suggesting that they could have CSC characteristics and the ability to induce EMT, as reported for breast cancer. Clinical specimens showed that overall survival was 39.4% and 57.8% (p = 0.045) and that progression-free survival was 27.6% and 51.6% (p = 0.013) for the high-expression and the low-expression groups, respectively, indicating poor prognosis for the high GPNMB group. The high GPNMB group was also more resistant to chemoradiation and bioradiotherapy. GPNMB was more highly expressed in metastatic lymph nodes than in the primary tumor.Conclusion: GPNMB-positive cells might have CSC characteristics and induce EMT. Detailed functional analyses of GPNMB in HNSCC and the establishment of therapies targeting GPNMB will lead to improved prognoses.

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Section: Discussionmentioning

confidence: 99%

GPNMB-Positive Cells in Head and Neck Squamous Cell Carcinoma—Their Roles in Cancer Stemness, Therapy Resistance, and Metastasis

Kawasaki¹,

Suzuki²,

Suzuki³

et al. 2022

Pathol. Oncol. Res.

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“…The efficacy and safety of CDX-011 as monotherapy were evaluated in phase II clinical trials in patients with metastatic TNBC, overexpressing glycoprotein NMB (NCT01997333). However, the primary endpoint of the trial was not met (PFS was similar to the control group undergoing capecitabine treatment), and there was no reduced toxicity when compared to capecitabine alone (Vahdat et al, 2021). Sacituzumab govitecan (IMMU-132) is an ADC that combines an anti-Trop-2 (anti-humanized antitrophoblast cell-surface antigen 2) antibody with SN-38, linked by a cleavable CLA2 linker.…”

Section: Antibody-drug Conjugatesmentioning

confidence: 99%

Immunotherapy in triple-negative breast cancer: Insights into tumor immune landscape and therapeutic opportunities

Ribeiro

Carvalho

Gonçalves

et al. 2022

Front. Mol. Biosci.

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Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer that represents 15–20% of breast tumors and is more prevalent in young pre-menopausal women. It is the subtype of breast cancers with the highest metastatic potential and recurrence at the first 5 years after diagnosis. In addition, mortality increases when a complete pathological response is not achieved. As TNBC cells lack estrogen, progesterone, and HER2 receptors, patients do not respond well to hormone and anti-HER2 therapies, and conventional chemotherapy remains the standard treatment. Despite efforts to develop targeted therapies, this disease continues to have a high unmet medical need, and there is an urgent demand for customized diagnosis and therapeutics. As immunotherapy is changing the paradigm of anticancer treatment, it arises as an alternative treatment for TNBC patients. TNBC is classified as an immunogenic subtype of breast cancer due to its high levels of tumor mutational burden and presence of immune cell infiltrates. This review addresses the implications of these characteristics for the diagnosis, treatment, and prognosis of the disease. Herein, the role of immune gene signatures and tumor-infiltrating lymphocytes as biomarkers in TNBC is reviewed, identifying their application in patient diagnosis and stratification, as well as predictors of efficacy. The expression of PD-L1 expression is already considered to be predictive of response to checkpoint inhibitor therapy, but the challenges regarding its value as biomarker are described. Moreover, the rationales for different formats of immunotherapy against TNBC currently under clinical research are discussed, and major clinical trials are highlighted. Immune checkpoint inhibitors have demonstrated clinical benefit, particularly in early-stage tumors and when administered in combination with chemotherapy, with several regimens approved by the regulatory authorities. The success of antibody–drug conjugates and research on other emerging approaches, such as vaccines and cell therapies, will also be addressed. These advances give hope on the development of personalized, more effective, and safe treatments, which will improve the survival and quality of life of patients with TNBC.

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“…Monomethyl auristatin E (MMAE), a synthetic dolastatin 10 analog, has been conjugated to the anti-CD30 monoclonal antibody and tested in several advanced-stage tumors, with good therapeutic efficacies achieved. Glembatumumab vedotin, an MMAE ADC, is undergoing preclinical and phase-I/II testing for breast cancer, recurrent/ refractory osteosarcoma, and advanced melanoma [ 194 , 195 , 196 , 197 ], while another MMAE ADC named brentuximab vedotin has been approved to treat anaplastic large-cell lymphoma and refractory Hodgkin lymphoma [ 198 , 199 , 200 , 201 ].…”

Section: Clinical Relevance Of Pi3k/akt-cytoskeleton Crosstalkmentioning

confidence: 99%

PI3K/AKT Signaling Tips the Balance of Cytoskeletal Forces for Cancer Progression

Deng

Leong

Datta

et al. 2022

Cancers

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The PI3K/AKT signaling pathway plays essential roles in multiple cellular processes, which include cell growth, survival, metabolism, and motility. In response to internal and external stimuli, the PI3K/AKT signaling pathway co-opts other signaling pathways, cellular components, and cytoskeletal proteins to reshape individual cells. The cytoskeletal network comprises three main components, which are namely the microfilaments, microtubules, and intermediate filaments. Collectively, they are essential for many fundamental structures and cellular processes. In cancer, aberrant activation of the PI3K/AKT signaling cascade and alteration of cytoskeletal structures have been observed to be highly prevalent, and eventually contribute to many cancer hallmarks. Due to their critical roles in tumor progression, pharmacological agents targeting PI3K/AKT, along with cytoskeletal components, have been developed for better intervention strategies against cancer. In our review, we first discuss existing evidence in-depth and then build on recent advances to propose new directions for therapeutic intervention.

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Glembatumumab vedotin for patients with metastatic, gpNMB overexpressing, triple-negative breast cancer (“METRIC”): a randomized multicenter study

Cited by 36 publications

References 34 publications

GPNMB-Positive Cells in Head and Neck Squamous Cell Carcinoma—Their Roles in Cancer Stemness, Therapy Resistance, and Metastasis

GPNMB-Positive Cells in Head and Neck Squamous Cell Carcinoma—Their Roles in Cancer Stemness, Therapy Resistance, and Metastasis

Immunotherapy in triple-negative breast cancer: Insights into tumor immune landscape and therapeutic opportunities

PI3K/AKT Signaling Tips the Balance of Cytoskeletal Forces for Cancer Progression

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