Everolimus in the Treatment of Metastatic Breast Cancer

Royce, Melanie; Osman, Diaa

doi:10.4137/bcbcr.s29268

Cited by 64 publications

(48 citation statements)

References 32 publications

(74 reference statements)

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“…Panobinostat in combination with bortezomib and dexamethasone has been approved for use in treatment-refractory myeloma patients(8). Additionally, everolimus (9) and everolimus plus exemestane (10) has been approved for treatment in breast cancer. Entinostat (MS-275, an HDACi) was given breakthrough status in combination with exemesthane after a phase II trial demonstrated improvements in progression free survival and overall survival (11) and is currently being evaluated in a phase III trial in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation

Simmons

Michalowski

Gamache

et al. 2017

Molecular Cancer Therapeutics

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Cancer treatments often require combinations of molecularly targeted agents to be effective. mTORi (rapamycin) and HDACi (MS-275/entinostat) inhibitors have been shown to be effective in limiting tumor growth, and here we define part of the cooperative action of this drug combination. More than 60 human cancer cell lines responded synergistically (CI<1) when treated with this drug combination compared to single agents. In addition, a breast cancer patient-derived xenograft, and a BCL-XL plasmacytoma mouse model both showed enhanced responses to the combination compared to single agents. Mice, bearing plasma cell tumors lived an average of 70 days longer on combination treatment compared to single agents. A set of 37 genes cooperatively affected (34 down-regulated; 3 up-regulated) by the combination responded pharmacodynamically in human myeloma cell lines, xenografts, and a P493 model, and were both enriched in tumors, and correlated with prognostic markers in myeloma patient datasets. Genes down-regulated by the combination were overexpressed in several untreated cancers (breast, lung, colon, sarcoma, head and neck, myeloma) compared to normal tissues. The MYC/E2F axis, identified by upstream regulator analyses and validated by immunoblots, was significantly inhibited by the drug combination in several myeloma cell lines. Furthermore, 88% of the 34 genes downregulated have MYC binding sites in their promoters, and the drug combination cooperatively reduced MYC half-life by 55% and increased degradation. Cells with MYC mutations were refractory to the combination. Thus, integrative approaches to understand drug synergy identified a clinically actionable strategy to inhibit MYC/E2F activity and tumor cell growth in vivo.

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Section: Introductionmentioning

confidence: 99%

Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation

Simmons

Michalowski

Gamache

et al. 2017

Molecular Cancer Therapeutics

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“…Everolimus was originally approved for renal cancer in 2009, as immunosuppressant during renal transplants in 2010 and for pancreatic cancer in 2011. A phase III clinical trial 'Breast Cancer Trial of Oral Everolimus-2 (BOLERO-2)' that included everolimus in combination with exemestane was successfully completed in 2012 leading to the approval of everolimus by US FDA for the treatment of HR + , HER2 − advanced metastatic cancers that are resistant to letrozole or anastrazole [125,126].…”

Section: Mtor Kinase Inhibitormentioning

confidence: 99%

Drug repurposing for breast cancer therapy: Old weapon for new battle

Aggarwal

Verma

Aggarwal

et al. 2021

Seminars in Cancer Biology

101

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Despite tremendous resources being invested in prevention and treatment, breast cancer remains a leading cause of cancer deaths in women globally. The available treatment modalities are very costly and produces severe side effects. Drug repurposing that relate to new uses for old drugs has emerged as a novel approach for drug development. Repositioning of old, clinically approved, off patent non-cancer drugs with known targets, into newer indication is like using old weapons for new battle. The advances in genomics, proteomics and information computational biology has facilitated the process of drug repurposing. Repositioning approach not only fastens the process of drug development but also offers more effective, cheaper, safer drugs with lesser/known side effects. During the last decade, drugs such as alkylating agents, anthracyclins, antimetabolite, CDK4/6 inhibitor, aromatase inhibitor, mTOR inhibitor and mitotic inhibitors has been repositioned for breast cancer treatment. The repositioned drugs have been successfully used for the treatment of most aggressive triple negative breast cancer. The literature review suggest that serendipity plays a major role in the drug development. This article describes the comprehensive overview of the current scenario of drug repurposing for the breast cancer treatment. The strategies as well as several examples of repurposed drugs are provided. The challenges associated with drug repurposing are discussed. Current breast cancer therapyUnlike a decade ago, clinicians today have multiple choices for breast cancer treatment depending on the size, stage, grade, metastatic behavior, aggressiveness and intrinsic molecular subtyping of tumor, age, menopausal status, overall health, comorbidities, and preferences of the patient [9-13]. Chemotherapy, hormone therapy, immunotherapy, radiotherapy, and surgery are the common modalities for breast cancer [10,14]. Primary choice of treatment usually includes surgery with the aim of complete resection of the major tumor mass on the first hand. Breast conserving (lumpectomy) and breast reconstruction surgeries, mastectomy or lymph node dissections are performed initially in the breast cancer patients [15]. Surgery may be preceded with the systemic neoadjuvant therapies in order to shrink the tumor for effective surgery and to maximize breast conservation. For example, in HER2+ cases, Trastuzumab (Herceptin) and Pertuzumab (Perjeta)

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“…(1) mTOR Inhibitors Rapamycin and its analogues (rapalogs, e.g., sirolimus, temsirolimus, everolimus), which inhibit mTORC1 activity, are considered the first clinical PI3K signaling inhibitors [88]. Although temsirolimus is FDA approved for treating advanced renal cell carcinoma and everolimus is approved for the treatment of advanced breast cancer, nonfunctional gastrointestinal and lung neuroendocrine tumors, and renal cell carcinoma, rapalogs are not yet approved for the treatment of EC and are under development [89][90][91].…”

Section: Pi3k/akt/mtor Signaling Pathway Inhibitorsmentioning

confidence: 99%

Pathogenesis and Clinical Management of Uterine Serous Carcinoma

Zhang

Kwan

Wong

et al. 2020

Cancers

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Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer that has not been well characterized. It accounts for less than 10% of all endometrial cancers and 80% of endometrial cancer-related deaths. Currently, staging surgery together with chemotherapy or radiotherapy, especially vaginal cuff brachytherapy, is the main treatment strategy for USC. Whole-exome sequencing combined with preclinical and clinical studies are verifying a series of effective and clinically accessible inhibitors targeting frequently altered genes, such as HER2 and PI3K3CA, in varying USC patient populations. Some progress has also been made in the immunotherapy field. The PD-1/PD-L1 pathway has been found to be activated in many USC patients, and clinical trials of PD-1 inhibitors in USC are underway. This review updates the progress of research regarding the molecular pathogenesis and putative clinical management of USC. Keywords: endometrial cancer; uterine serous carcinomaPrecis: Uterine serous cancer, although rare, is the most lethal type of uterine cancer. It has distinct molecular features and pathogenic pathways compared with other uterine cancer types Cancers 2020, 12, 686 2 of 21 heterogeneity, grade 3 EEC displays dissimilar features. Although a large number of grade 3 EEC cases show a serous-like phenotype, others display unequivocally endometrioid morphology [6,7]. Type II tumors are typically detected in women 70 years or older and carry a poor prognosis, high recurrence frequency, and much lower 5-year survival rate compared with type I tumors. In addition, type II tumors usually lack estrogen/progesterone receptors and do not respond to hormonal fluctuations [5].Among the type II tumors, uterine serous carcinoma (USC) is the most common subtype. This highly aggressive variant accounts for only 10% of all ECs but 80% of all EC-associated deaths [8,9]. The 5-year tumor-specific survival rate is 74% and 33% for early-and late-stage USC patients, respectively (and 89% and 77% for low-and high-grade EEC) [10]. Unlike type I EC, the risk of metastasis and recurrence of USC does not rely on primary tumor size or grade; this trait contributes to a low overall survival rate of 18% to 27%. Complete surgical staging is performed, comprising total hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection, followed by carboplatin and paclitaxel. In light of poor patient survival and high recurrence rates, the development of targeted therapies specific to USC pathway aberrations would aid in its management. However, conducting studies that focus solely on this rare subtype has been a constant challenge, making it difficult to determine optimal treatment strategies [9].

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Everolimus in the Treatment of Metastatic Breast Cancer

Cited by 64 publications

References 32 publications

Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation

Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation

Drug repurposing for breast cancer therapy: Old weapon for new battle

Pathogenesis and Clinical Management of Uterine Serous Carcinoma

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