RESUMO
BACKGROUND: ABP 215 is a biosimilar to the reference product, bevacizumab, and was one of the first biosimilars approved by Health Canada for the first-line treatment of metastatic colorectal cancer (mCRC). This study aimed to address gaps in real-world evidence (RWE) including patient characteristics, treatment safety (primary objective), and effectiveness (secondary objective) for first-line ABP 215 therapy in Canadian patients with mCRC. MATERIALS AND METHODS: Retrospective data were collected in 2 waves, at least 1 year (Wave 1) or 2 years (Wave 2) after commercial availability of ABP 215 at each participating site. RESULTS: A total of 75 patients from Wave 1 and 164 patients from Wave 2 treated with a minimum of 1 cycle of ABP 215 were included. At least one safety event of interest (EOI) was recorded for 34.7% of Wave 1 and 42.7% of Wave 2 patients. The median progression free survival (PFS) for Wave 1 and 2 patients were 9.47 (95% confidence interval [CI]: 6.71, 11.90) and 21.38 (95% CI: 15.82, not estimable) months, respectively. Median overall survival was not estimable for Wave 1 and was 26.45 months for Wave 2. CONCLUSION: The safety and effectiveness of ABP 215 observed in this real-world study were comparable to clinical trial findings and to other RWE with longer PFS in the current study.
Assuntos
Medicamentos Biossimilares , Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Bevacizumab , Medicamentos Biossimilares/efeitos adversos , Canadá/epidemiologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Retais/tratamento farmacológico , Estudos RetrospectivosRESUMO
Minimal Canadian data are available on the RAS testing rates, treatment patterns, and corresponding overall survival (OS) in metastatic colorectal cancer (mCRC) patients. We conducted a population-based cohort study of left-sided RAS wild-type (WT) mCRC patients diagnosed between 1 January 2014 and 31 December 2019, and who were treated with first-line (1L) chemotherapy plus the epidermal growth factor receptor inhibitor panitumumab, chemotherapy plus bevacizumab, or chemotherapy alone, in Alberta, Canada, using electronic medical records and administrative health system data. Of the 2721 patients identified with left-sided mCRC, 320 patients with RAS WT mCRC were treated with 1L systemic therapy: chemotherapy plus panitumumab (n = 64), chemotherapy plus bevacizumab (n = 52), or chemotherapy alone (n = 204). Only 65% and 39% of the 320 1L-treated patients initiated second- and third-line therapy, respectively. A total of 71% of individuals with treated left-sided mCRC underwent RAS testing. The median OS for mCRC patients with RAS WT left-sided tumours was higher for patients treated with 1L panitumumab plus chemotherapy (34.3 months; 95% CI: 23.8-39.6) than for patients who received 1L chemotherapy alone (30.0 months; 95% CI: 24.9-34.1) or 1L bevacizumab plus chemotherapy (25.6 months; 95% CI: 21.2-35.7). These findings highlight an unmet need in left-sided RAS WT mCRC, with relatively few individuals receiving a biologic agent in combination with chemotherapy in the 1L setting, a high rate of attrition between lines, and a need for increased RAS testing before treatment initiation.
RESUMO
LIM domain containing proteins are important regulators of diverse cellular processes, and play pivotal roles in regulating the actin cytoskeleton. Lipoma Preferred Partner (LPP) is a member of the zyxin family of LIM proteins that has long been characterized as a promoter of mesenchymal/fibroblast cell migration. More recently, LPP has emerged as a critical inducer of tumor cell migration, invasion and metastasis. LPP is thought to contribute to these malignant phenotypes by virtue of its ability to shuttle into the nucleus, localize to adhesions and, most recently, to promote invadopodia formation. In this review, we will examine the mechanisms through which LPP regulates the functions of adhesions and invadopodia, and discuss potential roles of LPP in mediating cellular responses to mechanical cues within these mechanosensory structures.
RESUMO
We have previously shown that lipoma preferred partner (LPP) mediates TGFß-induced breast cancer cell migration and invasion. Herein, we demonstrate that diminished LPP expression reduces circulating tumour cell numbers, impairs cancer cell extravasation and diminishes lung metastasis. LPP localizes to invadopodia, along with Tks5/actin, at sites of matrix degradation and at the tips of extravasating breast cancer cells as revealed by intravital imaging of the chick chorioallantoic membrane (CAM). Invadopodia formation, breast cancer cell extravasation and metastasis require an intact LPP LIM domain and the ability of LPP to interact with α-actinin. Finally, we show that Src-mediated LPP phosphorylation at specific tyrosine residues (Y245/301/302) is critical for invadopodia formation, breast cancer cell invasion and metastasis. Together, these data define a previously unknown function for LPP in the formation of invadopodia and reveal a requirement for LPP in mediating the metastatic ability of breast cancer cells.
Assuntos
Neoplasias da Mama/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas com Domínio LIM/metabolismo , Neoplasias Pulmonares/metabolismo , Podossomos/metabolismo , Quinases da Família src/metabolismo , Actinina/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular , Linhagem Celular Tumoral , Proteínas do Citoesqueleto/genética , Feminino , Humanos , Proteínas com Domínio LIM/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Camundongos , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Fosforilação , Ligação Proteica , Interferência de RNA , Especificidade por Substrato , Quinases da Família src/genéticaRESUMO
The translation initiation factor eIF4E is an oncogene that is commonly overexpressed in primary breast cancers and metastases. In this article, we report that a pharmacologic inhibitor of eIF4E function, ribavirin, safely and potently suppresses breast tumor formation. Ribavirin administration blocked the growth of primary breast tumors in several murine models and reduced the development of lung metastases in an invasive model. Mechanistically, eIF4E silencing or blockade reduced the invasiveness and metastatic capability of breast cancer cells in a manner associated with decreased activity of matrix metalloproteinase (MMP)-3 and MMP-9. Furthermore, eIF4E silencing or ribavirin treatment suppressed features of epithelial-to-mesenchymal transition, a process crucial for metastasis. Our findings offer a preclinical rationale to explore broadening the clinical evaluation of ribavirin, currently being tested in patients with eIF4E-overexpressing leukemia, as a strategy to treat solid tumors such as metastatic breast cancer.
Assuntos
Neoplasias da Mama/patologia , Movimento Celular , Fator de Iniciação 4E em Eucariotos/antagonistas & inibidores , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Fator de Iniciação 4E em Eucariotos/genética , Feminino , Humanos , Neoplasias Pulmonares/secundário , Metaloproteinase 9 da Matriz/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Ribavirina/uso terapêutico , Fator de Crescimento Transformador beta/farmacologiaRESUMO
Transforming growth factor ß (TGFß) is a potent modifier of the malignant phenotype in ErbB2-expressing breast cancers. We demonstrate that epithelial-derived breast cancer cells, which undergo a TGFß-induced epithelial-to-mesenchymal transition (EMT), engage signaling molecules that normally facilitate cellular migration and invasion of mesenchymal cells. We identify lipoma preferred partner (LPP) as an indispensable regulator of TGFß-induced migration and invasion of ErbB2-expressing breast cancer cells. We show that LPP re-localizes to focal adhesion complexes upon TGFß stimulation and is a critical determinant in TGFß-mediated focal adhesion turnover. Finally, we have determined that the interaction between LPP and α-actinin, an actin cross-linking protein, is necessary for TGFß-induced migration and invasion of ErbB2-expressing breast cancer cells. Thus, our data reveal that LPP, which is normally operative in cells of mesenchymal origin, can be co-opted by breast cancer cells during an EMT to promote their migration and invasion.
Assuntos
Actinina/metabolismo , Neoplasias da Mama/metabolismo , Movimento Celular , Proteínas do Citoesqueleto/metabolismo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas com Domínio LIM/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Complexos Multiproteicos/metabolismo , Receptor ErbB-2/biossíntese , Fator de Crescimento Transformador beta/metabolismo , Actinina/genética , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proteínas do Citoesqueleto/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Proteínas com Domínio LIM/genética , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Transgênicos , Complexos Multiproteicos/genética , Invasividade Neoplásica , Receptor ErbB-2/genética , Fator de Crescimento Transformador beta/farmacologiaRESUMO
The ErbB2 and TGFß signaling pathways cooperate to promote the migratory, invasive, and metastatic behavior of breast cancer cells. We previously demonstrated that ShcA is necessary for these synergistic interactions. Through a structure/function approach, we now show that the phosphotyrosine-binding, but not the Src homology 2, domain of ShcA is required for TGFß-induced migration and invasion of ErbB2-expressing breast cancer cells. We further demonstrate that the tyrosine phosphorylation sites within ShcA (Tyr(239)/Tyr(240) and Tyr(313)) transduce distinct and non-redundant signals that promote these TGFß-mediated effects. We demonstrate that Grb2 is required specifically downstream of Tyr(313), whereas the Tyr(239)/Tyr(240) phosphorylation sites require the Crk adaptor proteins to augment TGFß-induced migration and invasion. Furthermore, ShcA Tyr(313) phosphorylation enhances tumor cell survival, and ShcA Tyr(239)/Tyr(240) signaling promotes endothelial cell recruitment into ErbB2-expressing breast tumors in vivo, whereas all three ShcA tyrosine residues are required for efficient breast cancer metastasis to the lungs. Our data uncover a novel ShcA-dependent signaling axis downstream of TGFß and ErbB2 that requires both the Grb2 and Crk adaptor proteins to increase the migratory and invasive properties of breast cancer cells. In addition, signaling downstream of specific ShcA tyrosine residues facilitates the survival, vascularization, and metastatic spread of breast tumors.
Assuntos
Neoplasias da Mama/metabolismo , Neoplasias Mamárias Animais/metabolismo , Fosfotirosina/química , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Motivos de Aminoácidos , Animais , Movimento Celular , Sobrevivência Celular , Feminino , Humanos , Neoplasias Pulmonares/secundário , Camundongos , Invasividade Neoplásica , Metástase Neoplásica , Fosforilação , RNA Interferente Pequeno/metabolismo , Receptor ErbB-2/metabolismo , Transdução de Sinais , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de SrcRESUMO
Cooperation between the Neu/ErbB-2 and transforming growth factor beta (TGF-beta) signaling pathways enhances the invasive and metastatic capabilities of breast cancer cells; however, the underlying mechanisms mediating this synergy have yet to be fully explained. We demonstrate that TGF-beta induces the migration and invasion of mammary tumor explants expressing an activated Neu/ErbB-2 receptor, which requires signaling from autophosphorylation sites located in the C terminus. A systematic analysis of mammary tumor explants expressing Neu/ErbB-2 add-back receptors that couple to distinct signaling molecules has mapped the synergistic effect of TGF-beta-induced motility and invasion to signals emanating from tyrosine residues 1226/1227 and 1253 of Neu/ErbB-2. Given that the ShcA adaptor protein is known to interact with Neu/ErbB-2 through these residues, we investigated the importance of this signaling molecule in TGF-beta-induced cell motility and invasion. The reduction of ShcA expression rendered cells expressing activated Neu/ErbB-2, or add-back receptors signaling specifically through tyrosines 1226/1227 or 1253, unresponsive to TGF-beta-induced motility and invasion. In addition, a dominant-negative form of ShcA, lacking its three known tyrosine phosphorylation sites, completely abrogates the TGF-beta-induced migration and invasion of breast cancer cells expressing activated Neu/ErbB-2. Our results implicate signaling through the ShcA adaptor as a key component in the synergistic interaction between these pathways.