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1.
Breast Cancer Res ; 21(1): 146, 2019 12 18.
Article in English | MEDLINE | ID: mdl-31852484

ABSTRACT

BACKGROUND: Addition of CDK4/6 inhibitors (CDK4/6i) to endocrine therapy significantly increased progression-free survival, leading to their approval and incorporation into the metastatic breast cancer treatment paradigm. With these inhibitors being routinely used for patients with advanced estrogen receptor-positive (ER+) breast cancer, resistance to these agents and its impact on subsequent therapy needs to be understood. Considering the central role of ER in driving the growth of ER+ breast cancers, and thus endocrine agents being a mainstay in the treatment paradigm, the effects of prior CDK4/6i exposure on ER signaling and the relevance of ER-targeted therapy are important to investigate. The objective of this study was to evaluate the anti-tumor activity of elacestrant, a novel oral selective estrogen receptor degrader (SERD), in preclinical models of CDK4/6i resistance. METHODS: Elacestrant was evaluated as a single agent, and in combination with alpelisib or everolimus, in multiple in vitro models and patient-derived xenografts that represent acquired and "de novo" CDK4/6i resistance. RESULTS: Elacestrant demonstrated growth inhibition in cells resistant to all three approved CDK4/6i (palbociclib, abemaciclib, ribociclib) in both ESR1 wild-type and mutant backgrounds. Furthermore, we demonstrated that elacestrant, as a single agent and in combination, inhibited growth of patient-derived xenografts that have been derived from a patient previously treated with a CDK4/6i or exhibit de novo resistance to CDK4/6i. While the resistant lines demonstrate distinct alterations in cell cycle modulators, this did not affect elacestrant's anti-tumor activity. In fact, we observe that elacestrant downregulates several key cell cycle players and halts cell cycle progression in vitro and in vivo. CONCLUSIONS: We demonstrate that breast cancer tumor cells continue to rely on ER signaling to drive tumor growth despite exposure to CDK4/6i inhibitors. Importantly, elacestrant can inhibit this ER-dependent growth despite previously reported mechanisms of CDK4/6i resistance observed such as Rb loss, CDK6 overexpression, upregulated cyclinE1 and E2F1, among others. These data provide a scientific rationale for the evaluation of elacestrant in a post-CDK4/6i patient population. Additionally, elacestrant may also serve as an endocrine backbone for rational combinations to combat resistance.


Subject(s)
Breast Neoplasms/metabolism , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Drug Resistance, Neoplasm , Protein Kinase Inhibitors/pharmacology , Receptors, Estrogen/metabolism , Tetrahydronaphthalenes/pharmacology , Animals , Antineoplastic Agents , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Female , Humans , Mice , Models, Biological , Molecular Targeted Therapy , Xenograft Model Antitumor Assays
2.
Clin Cancer Res ; 23(16): 4793-4804, 2017 Aug 15.
Article in English | MEDLINE | ID: mdl-28473534

ABSTRACT

Purpose: Estrogen receptor-positive (ER+) breast cancers are typically treated with endocrine agents, and dependence on the ER pathway is often retained even after multiple rounds of antiestrogen therapy. Selective estrogen receptor degraders (SERD) are being developed as a strategy to more effectively target ER and exploit ER dependence in these cancers, which includes inhibiting both wild-type and mutant forms of ER. The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER+ breast cancer.Experimental Design: Elacestrant was evaluated as a single agent and in combination with palbociclib or everolimus in multiple ER+ breast cancer models, including several patient-derived xenograft models.Results: Elacestrant induces the degradation of ER, inhibits ER-mediated signaling and growth of ER+ breast cancer cell lines in vitro and in vivo, and significantly inhibits tumor growth of multiple PDX models. Furthermore, we demonstrate that elacestrant in combination with palbociclib or everolimus can lead to greater efficacy in certain contexts. Finally, elacestrant exhibits significant antitumor activity both as a single agent and in combination with palbociclib in two patient-derived breast cancer xenograft models harboring ESR1 mutations.Conclusions: These data underscore the potential clinical utility of elacestrant as a single agent and as a combination therapy, for both early- and late-stage ER+ disease. Clin Cancer Res; 23(16); 4793-804. ©2017 AACR.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Tetrahydronaphthalenes/pharmacology , Xenograft Model Antitumor Assays , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Everolimus/administration & dosage , Female , Humans , MCF-7 Cells , Mice, Inbred BALB C , Mice, Nude , Piperazines/administration & dosage , Pyridines/administration & dosage , Receptors, Estrogen/genetics , Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/administration & dosage , Selective Estrogen Receptor Modulators/pharmacology , Tetrahydronaphthalenes/administration & dosage , Tumor Burden/drug effects
3.
J Cachexia Sarcopenia Muscle ; 6(4): 317-24, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26672741

ABSTRACT

BACKGROUND: Cancer-related weight loss is associated with increased inflammation and decreased survival. The novel inflammatory mediator growth differentiation factor (GDF)15 is associated with poor prognosis in cancer but its role in cancer-related weight loss (C-WL) remains unclear. Our objective was to measure GDF15 in plasma samples of cancer subjects and controls and establish its association with other inflammatory markers and clinical outcomes. METHODS: We measured body weight, appetite, plasma GDF15, and other inflammatory markers in men with cancer-related weight loss (C-WL, n = 58), weight stable patients with cancer (C-WS, n = 72), and non-cancer controls (Co, n = 59) matched by age and pre-illness body mass index. In a subset of patients we also measured handgrip strength, appendicular lean body mass (aLBM), Eastern Cooperative Oncology Group (ECOG), and Karnofsky performance scores. RESULTS: GDF15, interleukin (IL)-6 and IL-8 were increased in C-WL versus other groups. IL-1 receptor antagonist, IL-4, interferon-gamma, tumour necrosis factor alpha, and vascular endothelial growth factor A were increased in C-WL versus C-WS, and Activin A was significantly downregulated in Co versus other groups. C-WL patients had lower handgrip strength, aLBM, and fat mass, and Eastern Cooperative Oncology Group and Karnofsky performance scores were lower in both cancer groups. GDF15, IL-6, and IL-8 significantly correlated with weight loss; GDF15 negatively correlated with aLBM, handgrip strength, and fat mass. IL-8 and Activin A negatively correlated with aLBM and fat mass. GDF15 and IL-8 predicted survival adjusting for stage and weight change (Cox regression P < 0.001 for both). CONCLUSION: GDF15 and other inflammatory markers are associated with weight loss, decreased aLBM and strength, and poor survival in patients with cancer. GDF15 may serve as a prognostic indicator in cancer patients and is being evaluated as a potential therapeutic target for cancer-related weight loss.

4.
Mol Cancer Ther ; 9(10): 2652-64, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20924128

ABSTRACT

Insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) and critical activator of the phosphatidylinositol 3-kinase-AKT pathway. IGF-1R is required for oncogenic transformation and tumorigenesis. These observations have spurred anticancer drug discovery and development efforts for both biological and small-molecule IGF-1R inhibitors. The ability for one RTK to compensate for another to maintain tumor cell viability is emerging as a common resistance mechanism to antitumor agents targeting individual RTKs. As IGF-1R is structurally and functionally related to the insulin receptor (IR), we asked whether IR is tumorigenic and whether IR-AKT signaling contributes to resistance to IGF-1R inhibition. Both IGF-1R and IR(A) are tumorigenic in a mouse mammary tumor model. In human tumor cells coexpressing IGF-1R and IR, bidirectional cross talk was observed following either knockdown of IR expression or treatment with a selective anti-IGF-1R antibody, MAB391. MAB391 treatment resulted in a compensatory increase in phospho-IR, which was associated with resistance to inhibition of IRS1 and AKT. In contrast, treatment with OSI-906, a small-molecule dual inhibitor of IGF-1R/IR, resulted in enhanced reduction in phospho-IRS1/phospho-AKT relative to MAB391. Insulin or IGF-2 activated the IR-AKT pathway and decreased sensitivity to MAB391 but not to OSI-906. In tumor cells with an autocrine IGF-2 loop, both OSI-906 and an anti-IGF-2 antibody reduced phospho-IR/phospho-AKT, whereas MAB391 was ineffective. Finally, OSI-906 showed superior efficacy compared with MAB391 in human tumor xenograft models in which both IGF-1R and IR were phosphorylated. Collectively, these data indicate that cotargeting IGF-1R and IR may provide superior antitumor efficacy compared with targeting IGF-1R alone.


Subject(s)
Receptor, IGF Type 1/metabolism , Receptor, Insulin/metabolism , Animals , Blotting, Western , Cell Line, Tumor , Imidazoles/pharmacology , Mammary Neoplasms, Experimental/drug therapy , Mice , Phosphorylation , Polymerase Chain Reaction , Pyrazines/pharmacology , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, Insulin/antagonists & inhibitors , Signal Transduction
5.
Cancer Res ; 68(2): 561-70, 2008 Jan 15.
Article in English | MEDLINE | ID: mdl-18199553

ABSTRACT

The alpha(v)beta(6) integrin is up-regulated on epithelial malignancies and has been implicated in various aspects of cancer progression. Immunohistochemical analysis of alpha(v)beta(6) expression in 10 human tumor types showed increased expression relative to normal tissues. Squamous carcinomas of the cervix, skin, esophagus, and head and neck exhibited the highest frequency of expression, with positive immunostaining in 92% (n = 46), 84% (n = 49), 68% (n = 56), and 64% (n = 100) of cases, respectively. We studied the role of alpha(v)beta(6) in Detroit 562 human pharyngeal carcinoma cells in vitro and in vivo. Prominent alpha(v)beta(6) expression was detected on tumor xenografts at the tumor-stroma interface resembling the expression on human head and neck carcinomas. Nonetheless, coculturing cells in vitro with matrix proteins did not up-regulate alpha(v)beta(6) expression. Detroit 562 cells showed alpha(v)beta(6)-dependent adhesion and activation of transforming growth factor-beta (TGF-beta) that was inhibited >90% with an alpha(v)beta(6) blocking antibody, 6.3G9. Although both recombinant soluble TGF-beta receptor type-II (rsTGF-beta RII-Fc) and 6.3G9 inhibited TGF-beta-mediated Smad2/3 phosphorylation in vitro, there was no effect on proliferation. Conversely, in vivo, 6.3G9 and rsTGF-beta RII-Fc inhibited xenograft tumor growth by 50% (n = 10, P < 0.05) and >90% (n = 10, P < 0.001), respectively, suggesting a role for the microenvironment in this response. However, stromal collagen and smooth muscle actin content in xenograft sections were unchanged with treatments. Although further studies are required to consolidate in vitro and in vivo results and define the mechanisms of tumor inhibition by alpha(v)beta(6) antibodies, our findings support a role for alpha(v)beta(6) in human cancer and underscore the therapeutic potential of function blocking alpha(v)beta(6) antibodies.


Subject(s)
Antibodies, Monoclonal/pharmacology , Carcinoma, Squamous Cell/pathology , Cell Proliferation/drug effects , Integrin alpha5/immunology , Pharyngeal Neoplasms/pathology , Transforming Growth Factor beta/physiology , Animals , Carcinoma, Squamous Cell/metabolism , Cells, Cultured , Disease Progression , Female , Humans , Immunoglobulin Fc Fragments/pharmacology , Integrin alpha5/metabolism , Integrin alpha5/physiology , Mice , Mice, Nude , Mink , Pharyngeal Neoplasms/metabolism , Protein Isoforms/immunology , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/pharmacology , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/chemistry , Recombinant Fusion Proteins/pharmacology , Signal Transduction/genetics , Smad Proteins/metabolism , Xenograft Model Antitumor Assays
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