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Connecting scientific concepts with clinical applications is an important objective of pharmacy education. As the field of precision oncology expands, it is critical for pharmacy students to understand how genetic information informs cancer treatment decisions. However, to effectively teach students about pharmacogenomics and pharmacogenetics, faculty require relevant educational resources, including those that support higher-order learning. In this Commentary, we demonstrate the potential utility of publicly accessible cancer genomics databases as teaching resources for pharmacogenomics and pharmacogenetics in oncology pharmacy education. Using clinical data retrieved from a genomics database, we illustrate how case studies can be developed to target core competencies, including understanding tumor genomics profiling, somatic mutations and pharmacotherapy selection, and clinical pharmacogenetics testing. Cancer genomics databases provide readily available, cost-effective, clinical data resources that support active learning related to pharmacogenomics and pharmacogenetics education in oncology pharmacy curricula.
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Educación en Farmacia , Neoplasias , Estudiantes de Farmacia , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Medicina de Precisión , Farmacogenética/educación , Genómica/educaciónRESUMEN
Aberrations in DNA damage response genes are recognized mediators of tumorigenesis and resistance to chemo- and radiotherapy. While protein phosphatase magnesium-dependent 1 δ (PPM1D), located on the long arm of chromosome 17 at 17q22-23, is a key regulator of cellular responses to DNA damage, amplification, overexpression, or mutation of this gene is important in a wide range of pathologic processes. In this review, we describe the physiologic function of PPM1D, as well as its role in diverse processes, including fertility, development, stemness, immunity, tumorigenesis, and treatment responsiveness. We highlight both the advances and limitations of current approaches to targeting malignant processes mediated by pathogenic alterations in PPM1D with the goal of providing rationale for continued research and development of clinically viable treatment approaches for PPM1D-associated diseases.
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Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Terapia Molecular Dirigida/métodos , Proteína Fosfatasa 2C/antagonistas & inhibidores , Proteína Fosfatasa 2C/fisiología , Animales , Ciclo Celular , Daño del ADN , Femenino , Fertilidad/fisiología , Regulación del Desarrollo de la Expresión Génica , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/fisiología , Humanos , Masculino , RatonesRESUMEN
[This corrects the article DOI: 10.18632/oncotarget.21765.].
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BACKGROUND: The tumor immune microenvironment plays a critical role in the prognosis and outcome of breast cancers. This study examined the role of tumor-infiltrating lymphocytes (TILs), CD8+, FOXP3+ lymphocytes, PD-L1 expression, and other clinicopathological parameters in HER2+ breast cancer and correlate with tumor response to neoadjuvant therapy. METHODS: We included 173 HER2+ patients treated with neoadjuvant HER2-targeted chemotherapy regimens from 2010 to 2016. 67 cases had biopsy blocks to evaluate TIL, CD8, FOXP3, and PD-L1 immunohistochemistry staining. Tumors were classified as pCR vs non-pCR group. Clinicopathological parameters, TIL, CD8+ and FOXP3+ cell count, and PD-L1 expression were correlated with pCR rate. RESULTS: Univariate analyses showed that pCR rate was significantly correlated with low PR, low ER, high Ki-67, high FOXP3, HER2 IHC3+ , high HER2 ratio and copy number. By multivariate analysis, Ki-67 was the only variable significantly correlated with pCR. PD-L1 expression was detected in 9.2% cases. TIL hotspot has a non-significant correlation with pCR rate (p = 0.096). CONCLUSIONS: High Ki-67 is a strong predictor for pCR in HER2+ breast cancer. TIL and FOXP3 T cells may play a role in tumor response in HER2+ cancer. PD-L1 is expressed in a subset of HER2+ breast cancer, supporting a role of immunotherapy in treating a subset of HER2+ breast cancers. The role of PD-L1, TIL, and other markers of immunogenicity as predictors of response to neoadjuvant chemotherapy in HER2+ breast cancer should be further evaluated.
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Neoplasias de la Mama , Terapia Neoadyuvante , Antígeno B7-H1/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Linfocitos T CD8-positivos , Femenino , Factores de Transcripción Forkhead/genética , Humanos , Linfocitos Infiltrantes de Tumor , Pronóstico , Microambiente TumoralRESUMEN
BACKGROUND: HER2-targeted neoadjuvant therapy has high efficacy in treating HER2-positive breast cancer. Response to neoadjuvant therapy helps clinicians make treatment decisions and make estimates about prognosis. This study examined clinicopathologic features to determine which may be most predictive of response to neoadjuvant therapy in HER2+ breast cancer. PATIENTS AND METHODS: Patients with HER2+ breast cancer (n = 173) who had an initial biopsy performed between 2010 and 2016 were identified at our institution. Tumor response was evaluated on excisional specimens using the MD Anderson residual cancer burden (RCB) classification. Tumors with pathologic complete response (defined as no residual invasive carcinoma in the breast and lymph nodes) and RCB-I were classified as having response and tumors with RCB-II and -III as having no response. Patient age, tumor size, nuclear grade (1/2 vs. 3), mitosis, Nottingham grade, HER2 immunohistochemistry (1/2+ vs. 3+), HER2/CEP17 (chromosome enumeration probe 17) ratio, HER2 copy number, estrogen receptor, progesterone receptor, Ki-67, and tumor-infiltrating lymphocytes (TIL) were evaluated and correlated with response. TILs were evaluated for an average and also for the hot spot/total tumor stromal ratio. RESULTS: Small tumor size, low estrogen receptor and progesterone receptor expression, HER2 immunohistochemistry 3+, high Ki-67, high HER2/CEP17 ratio, and high HER2 copy number were significantly associated with response (all P < .05). TIL hot spot was associated with RCB in univariate (P < .05) but not multivariate analyses. CONCLUSION: Clinicopathologic features may help predict HER2+ breast cancer response to neoadjuvant therapy. Larger studies would be useful to confirm these associations, which may have relevance to clinical practice.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/terapia , Terapia Neoadyuvante/métodos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Mama/inmunología , Mama/patología , Mama/cirugía , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/mortalidad , Quimioterapia Adyuvante/métodos , Variaciones en el Número de Copia de ADN , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/inmunología , Estudios de Factibilidad , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Mastectomía , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Supervivencia sin Progresión , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/análisis , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/análisis , Receptores de Progesterona/metabolismo , Carga TumoralRESUMEN
BACKGROUND: Children with diffuse intrinsic pontine glioma (DIPG) succumb to disease within 2 years of diagnosis despite treatment with ionizing radiation (IR) and/or chemotherapy. Our aim was to determine the role of protein phosphatase, magnesium-dependent 1, delta (PPM1D) mutation, present in up to 25% of cases, in DIPG pathogenesis and treatment. METHODS: Using genetic and pharmacologic approaches, we assayed effects of PPM1D mutation on DIPG growth and murine survival. We assayed effects of targeting mutated PPM1D alone or with IR on signaling, cell cycle, proliferation, and apoptosis in patient-derived DIPG cells in vitro, in organotypic brain slices, and in vivo. RESULTS: PPM1D-mutated DIPG cell lines exhibited increased proliferation in vitro and in vivo, conferring reduced survival in orthotopically xenografted mice, through stabilization of truncated PPM1D protein and inactivation of DNA damage response (DDR) effectors p53 and H2A.X. PPM1D knockdown or treatment with PPM1D inhibitors suppressed growth of PPM1D-mutated DIPGs in vitro. Orthotopic xenografting of PPM1D short hairpin RNA-transduced or PPM1D inhibitor-treated, PPM1D-mutated DIPG cells into immunodeficient mice resulted in reduced tumor proliferation, increased apoptosis, and extended mouse survival. PPM1D inhibition had similar effects to IR alone on DIPG growth inhibition and augmented the anti-proliferative and pro-apoptotic effects of IR in PPM1D-mutated DIPG models. CONCLUSIONS: PPM1D mutations inactivate DDR and promote DIPG growth. Treatment with PPM1D inhibitors activated DDR pathways and enhanced the anti-proliferative and pro-apoptotic effects of IR in DIPG models. Our results support continued development of PPM1D inhibitors for phase I/II trials in children with DIPG.
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Neoplasias del Tronco Encefálico/radioterapia , Daño del ADN/efectos de la radiación , Glioma Pontino Intrínseco Difuso/radioterapia , Proteínas Mutantes/antagonistas & inhibidores , Mutación , Proteína Fosfatasa 2C/antagonistas & inhibidores , Radiación Ionizante , Animales , Apoptosis , Neoplasias del Tronco Encefálico/genética , Neoplasias del Tronco Encefálico/patología , Ciclo Celular , Movimiento Celular , Proliferación Celular , Glioma Pontino Intrínseco Difuso/genética , Glioma Pontino Intrínseco Difuso/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Proteína Fosfatasa 2C/genética , Proteína Fosfatasa 2C/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Breast cancer continues to be the most commonly diagnosed malignancy and second most common cause of cancer-related deaths among women in the United States. Improved understanding of the molecular heterogeneity of breast tumors and the approval of multiple targeted therapies have revolutionized the treatment landscape and long-term survival rates for patients with breast cancer. Despite the development of highly effective targeted agents, drug resistance and disease progression remain major clinical concerns. Improved understanding of the molecular mechanisms mediating drug resistance will allow new treatments to be developed. The forkhead box M1 (FoxM1) transcription factor is overexpressed in breast cancer and strongly associated with resistance to targeted therapies and chemotherapy. FoxM1 regulates all hallmarks of cancer, including proliferation, mitosis, EMT, invasion, and metastasis. Inhibition of FoxM1 transcription factor function is a potential strategy for overcoming breast cancer progression. In this research update, we review the role of FoxM1 in breast cancer and pharmacological approaches for blocking FoxM1 transcription factor function. Future preclinical studies should evaluate combination drug strategies to inhibit FoxM1 function and upstream kinase signaling pathways as potential strategies to treat resistant and metastatic breast cancers.
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Antineoplásicos/administración & dosificación , Antineoplásicos/metabolismo , Neoplasias de la Mama/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Proteína Forkhead Box M1/antagonistas & inhibidores , Proteína Forkhead Box M1/biosíntesis , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Resistencia a Antineoplásicos/fisiología , Femenino , Proteína Forkhead Box M1/genética , Regulación Neoplásica de la Expresión Génica , HumanosRESUMEN
INTRODUCTION: Approval of the HER2-targeted antibody trastuzumab dramatically improved outcomes for patients with HER2-positive breast cancer. Multiple trastuzumab biosimilars, including ABP 980, are in clinical development. Biosimilars are not identical to the reference biologic, but exhibit equivalence and safety in analytical and clinical studies. Areas covered: A brief introduction to trastuzumab, overview of trastuzumab biosimilars, and detailed review of ABP 980 preclinical and clinical studies are included. We searched PubMed and 2016-2017 ASCO and ESMO conference proceedings for 'ABP 980' or 'trastuzumab biosimilar'. 'ABP 980 and breast cancer' or 'trastuzumab biosimilar and breast cancer' were used to search clinicaltrials.gov for phase III trials. Analytical studies of ABP 980 pharmacokinetics (PK) or pharmacodynamics (PD), phase I studies of ABP 980 safety and PK/PD, and phase III studies of clinical efficacy vs trastuzumab are included. Expert opinion: Questions remain regarding long-term impact of biosimilars on overall healthcare costs, insurance coverage of multiple approved biosimilars, and extensive clinical safety and efficacy follow-up. By producing a competitive market, trastuzumab biosimilars are anticipated to improve access to standard of care therapies, although real-world evidence remains to be obtained. Increased global access to HER2-targeted therapy may eventually alter the landscape of breast cancer and survival rates.
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Biosimilares Farmacéuticos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Anemia/etiología , Anticuerpos Antiidiotipos/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Biosimilares Farmacéuticos/efectos adversos , Biosimilares Farmacéuticos/farmacocinética , Ensayos Clínicos como Asunto , Femenino , Humanos , Receptor ErbB-2/inmunología , Receptor ErbB-2/metabolismo , Trastuzumab/efectos adversos , Trastuzumab/farmacocinética , Trastuzumab/uso terapéuticoRESUMEN
Expression of the inflammatory cytokine growth differentiation factor 15 (GDF15) is significantly elevated in many tumor types in association with epithelial mesenchymal transition (EMT), drug resistance, and progressive disease. However, few studies have examined GDF15 expression, signaling, or function in breast cancer. In the current study, we demonstrate that GDF15 is associated with high tumor grade, ER-negativity, and HER2 overexpression in patients with breast cancer. Stable overexpression of GDF15 upregulates expression of mesenchymal markers and transcription factors, including FoxM1, and increases cellular invasion. GDF15 stable clones and breast cancer cells stimulated with recombinant human GDF15 (rhGDF15) demonstrate activation of insulin-like growth factor-1 receptor (IGF-1R), EMT, and invasion. Pharmacologic inhibition of IGF-1R reduces GDF15-mediated EMT and invasion in stable clones, and FoxM1 knockdown rescues invasion and EMT in GDF15 stable clones and rhGDF15-stimulated cells. These data suggest that IGF-1R-FoxM1 signaling is a potential mechanism through which GDF15 drives EMT and invasion of breast cancers. Further, GDF15 knockdown significantly inhibits invasion of HER2-overexpressing and triple-negative breast cancer cells, supporting further preclinical investigation of GDF15-targeted therapies.
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Previously we found that the estrogen receptor (ER) related factor ERRF regulates cell proliferation and tumor growth, and its expression is positively associated with ER status and better survival but inversely associated with ERBB2 (also named HER2) status in breast cancer. Here we report that ERRF also plays an important role in the response of ERBB2-positive breast cancer cells to lapatinib, a dual tyrosine kinase inhibitor that interrupts the ERBB2 and EGFR pathway. In ERBB2-positive breast cancer cell lines, lower levels of ERRF expression correlated with lapatinib resistance, restoration of ERRF expression in lapatinib-resistant cell lines JIMT-1 and MDA-MB-453 enhanced their lapatinib responses, and knockdown of ERRF in lapatinib sensitive cell lines BT-474 and SK-BR-3 caused lapatinib resistance. ERRF-enhanced lapatinib sensitivity was also confirmed in xenograft tumors of JIMT-1 cells. In patients with ERBB2-positive breast cancer, higher level of ERRF expression correlated with both pathologic complete response (pCR) to lapatinib and better survival. Mechanistically, ERRF expression in resistant cells promoted lapatinib-induced apoptosis by attenuating MCL1 and ERBB2 expression. These results suggest that ERRF plays an important role in lapatinib response of ERBB2-positive breast cancer, and further study of ERRF could lead to improved prediction and sensitivity of lapatinib response.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteínas Nucleares/metabolismo , Quinazolinas/uso terapéutico , Receptor ErbB-2/metabolismo , Animales , Apoptosis , Neoplasias de la Mama/mortalidad , Línea Celular Tumoral , Resistencia a Antineoplásicos , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Lapatinib , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteínas Nucleares/genética , ARN Interferente Pequeño/genética , Receptor ErbB-2/genética , Transducción de Señal , Análisis de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Despite the promise of targeted therapies, there remains an urgent need for effective treatment for esophageal cancer (EC) and triple-negative breast cancer (TNBC). Current FDA-approved drugs have significant problems of toxicity, safety, selectivity, efficacy and development of resistance. In this manuscript, we demonstrate that rationally designed peptide vaccines/mimics are a viable therapeutic strategy for blocking aberrant molecular signaling pathways with high affinity, specificity, potency and safety. Specifically, we postulate that novel combination treatments targeting members of the EGFR family and IGF-1R will yield significant anti-tumor effects in in vitro models of EC and TNBC possibly overcoming mechanisms of resistance. We show that the combination of HER-1 and HER-2 or HER-1 and IGF-1R peptide mimics/vaccine antibodies exhibited enhanced antitumor properties with significant inhibition of tumorigenesis in OE19 EC and MDA-MB-231 TNBC cell lines. Our work elucidates the mechanisms of HER-1/IGF-1R and HER-1/HER-2 signaling in these cancer cell lines, and the promising results support the rationale for dual targeting with HER-1 and HER-2 or IGF-1R as an improved treatment regimen for advanced therapy tailored to difference types of cancer.
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As part of the Halifax Project, this review brings attention to the potential effects of environmental chemicals on important molecular and cellular regulators of the cancer hallmark of evading growth suppression. Specifically, we review the mechanisms by which cancer cells escape the growth-inhibitory signals of p53, retinoblastoma protein, transforming growth factor-beta, gap junctions and contact inhibition. We discuss the effects of selected environmental chemicals on these mechanisms of growth inhibition and cross-reference the effects of these chemicals in other classical cancer hallmarks.
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Exposición a Riesgos Ambientales/efectos adversos , Sustancias Peligrosas/efectos adversos , Neoplasias/inducido químicamente , Neoplasias/etiología , Animales , Humanos , Transducción de Señal/efectos de los fármacosRESUMEN
Triple negative breast cancer (TNBC) is a highly metastatic disease that currently lacks effective prevention and treatment strategies. The insulin-like growth factor 1 receptor (IGF1R) and focal adhesion kinase (FAK) signaling pathways function in numerous developmental processes, and alterations in both are linked with a number of common pathological diseases. Overexpression of IGF1R and FAK are closely associated with metastatic breast tumors. The present study investigated the interrelationship between IGF1R and FAK signaling in regulating the malignant properties of TNBC cells. Using small hairpin RNA (shRNA)-mediated IGF1R silencing methods, we showed that IGF1R is essential for sustaining mesenchymal morphologies of TNBC cells and modulates the expression of EMT-related markers. We further showed that IGF1R overexpression promotes migratory and invasive behaviors of TNBC cell lines. Most importantly, IGF1R-driven migration and invasion is predominantly mediated by FAK activation and can be suppressed using pharmacological inhibitors of FAK. Our findings in TNBC cells demonstrate a novel role of the IGF1R/FAK signaling pathway in regulating critical processes involved in the metastatic cascade. These results may improve the current understanding of the basic molecular mechanisms of TNBC metastasis and provide a strong rationale for co-targeting of IGF1R and FAK as therapy for mesenchymal TNBCs.
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Movimiento Celular , Proliferación Celular , Transición Epitelial-Mesenquimal , Quinasa 1 de Adhesión Focal/metabolismo , Células Madre Mesenquimatosas/patología , Receptor IGF Tipo 1/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Apoptosis , Western Blotting , Femenino , Quinasa 1 de Adhesión Focal/antagonistas & inhibidores , Quinasa 1 de Adhesión Focal/genética , Humanos , Técnicas para Inmunoenzimas , Células Madre Mesenquimatosas/metabolismo , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor IGF Tipo 1/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Células Tumorales CultivadasRESUMEN
The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting.
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Carcinogénesis/genética , Proliferación Celular/genética , Neoplasias/genética , Neoplasias/terapia , Transducción de Señal , Proteínas de Unión al ADN , Factor 15 de Diferenciación de Crecimiento/genética , Vía de Señalización Hippo , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Terapia Molecular Dirigida , Proteínas Nucleares/genética , Fosfohidrolasa PTEN/genética , Proteínas Serina-Treonina Quinasas/genética , Proteína de Retinoblastoma/genética , Somatomedinas/genética , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Resistance to the human epidermal growth factor receptor (HER2)-targeted antibody trastuzumab is a major clinical concern in the treatment of HER2-positive metastatic breast cancer. Increased expression or signaling from the insulin-like growth factor-1 receptor (IGF-1R) has been reported to be associated with trastuzumab resistance. However, the specific molecular and biologic mechanisms through which IGF-1R promotes resistance or disease progression remain poorly defined. In this study, we found that the major biologic effect promoted by IGF-1R was invasion, which was mediated by both Src-focal adhesion kinase (FAK) signaling and Forkhead box protein M1 (FoxM1). Cotargeting IGF-1R and HER2 using either IGF-1R antibodies or IGF-1R short hairpin RNA in combination with trastuzumab resulted in significant but modest growth inhibition. Reduced invasion was the most significant biologic effect achieved by cotargeting IGF-1R and HER2 in trastuzumab-resistant cells. Constitutively active Src blocked the anti-invasive effect of IGF-1R/HER2 cotargeted therapy. Furthermore, knockdown of FoxM1 blocked IGF-1-mediated invasion, and dual targeting of IGF-1R and HER2 reduced expression of FoxM1. Re-expression of FoxM1 restored the invasive potential of IGF-1R knockdown cells treated with trastuzumab. Overall, our results strongly indicate that therapeutic combinations that cotarget IGF-1R and HER2 may reduce the invasive potential of cancer cells that are resistant to trastuzumab through mechanisms that depend in part on Src and FoxM1.
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Neoplasias de la Mama/metabolismo , Quinasa 1 de Adhesión Focal/biosíntesis , Factores de Transcripción Forkhead/biosíntesis , Regulación Neoplásica de la Expresión Génica , Receptor ErbB-2/biosíntesis , Receptor IGF Tipo 1/biosíntesis , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Proteína Forkhead Box M1 , Genes src/fisiología , Humanos , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/genética , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/genética , Transducción de Señal/fisiologíaRESUMEN
Trastuzumab-based chemotherapy has dramatically improved outcomes for patients with all stages of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Additional HER2-directed agents that have recently been approved are also expected to improve outcomes. Patients with small, lymph node-negative, HER2-positive breast cancers who are treated with trastuzumab-based chemotherapy demonstrate especially favorable responses, with 5-year recurrence rates of <5%. In this review, recent data regarding response rates among patients with early-stage HER2-positive breast cancer treated with trastuzumab-based chemotherapy are discussed. This review supports future studies of the possible omission of chemotherapy in a subset of patients with HER2-positive cancers, specifically those that coexpress hormone receptors.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/tratamiento farmacológico , Receptor ErbB-2/análisis , Neoplasias de la Mama/química , Neoplasias de la Mama/prevención & control , Quimioterapia Adyuvante , Ensayos Clínicos como Asunto , Docetaxel , Femenino , Humanos , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Taxoides/administración & dosificación , Trastuzumab , Resultado del TratamientoRESUMEN
The human epidermal growth factor receptor 3 (HER-3/ErbB3) is a unique member of the human epidermal growth factor family of receptors, because it lacks intrinsic kinase activity and ability to heterodimerize with other members. HER-3 is frequently upregulated in cancers with epidermal growth factor receptor (EGFR/HER-1/ErbB1) or human epidermal growth factor receptor 2 (HER-2/ErBB2) overexpression, and targeting HER-3 may provide a route for overcoming resistance to agents that target EGFR or HER-2. We have previously developed vaccines and peptide mimics for HER-1, HER-2 and vascular endothelial growth factor (VEGF). In this study, we extend our studies by identifying and evaluating novel HER-3 peptide epitopes encompassing residues 99-122, 140-162, 237-269 and 461-479 of the HER-3 extracellular domain as putative B-cell epitopes for active immunotherapy against HER-3 positive cancers. We show that the HER-3 vaccine antibodies and HER-3 peptide mimics induced antitumor responses: inhibition of cancer cell proliferation, inhibition of receptor phosphorylation, induction of apoptosis and antibody dependent cellular cytotoxicity (ADCC). Two of the HER-3 epitopes 237-269 (domain II) and 461-479 (domain III) significantly inhibited growth of xenografts originating from both pancreatic (BxPC3) and breast (JIMT-1) cancers. Combined therapy of HER-3 (461-471) epitope with HER-2 (266-296), HER-2 (597-626), HER-1 (418-435) and insulin-like growth factor receptor type I (IGF-1R) (56-81) vaccine antibodies and peptide mimics show enhanced antitumor effects in breast and pancreatic cancer cells. This study establishes the hypothesis that combination immunotherapy targeting different signal transduction pathways can provide effective antitumor immunity and long-term control of HER-1 and HER-2 overexpressing cancers.
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The insulin-like growth factor-1 receptor (IGF-1R) plays a crucial role in cellular growth, proliferation, transformation, and inhibition of apoptosis. A myriad of human cancer types have been shown to overexpress IGF-1R, including breast and pancreatic adenocarcinoma. IGF-1R signaling interferes with numerous receptor pathways, rendering tumor cells resistant to chemotherapy, anti-hormonal therapy, and epidermal growth factor receptor (EGFR, also known as HER-1) and v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2, (ERBB2, best known as HER-2) -targeted therapies. Targeting the IGF:IGF-1R axis with innovative peptide inhibitors and vaccine antibodies thus represents a promising therapeutic strategy to overcome drug resistance and to provide new avenues for individualized and combinatorial treatment strategies. In this study, we designed, synthesized, and characterized several B-cell epitopes from the IGF-1:IGF-1R axis. The chimeric peptide epitopes were highly immunogenic in outbred rabbits, eliciting high levels of peptide vaccine antibodies. The IGF-1R peptide antibodies and peptide mimics inhibited cell proliferation and receptor phosphorylation, induced apoptosis and antibody-dependent cellular cytotoxicity (ADCC), and significantly inhibited tumor growth in the transplantable BxPC-3 pancreatic and JIMT-1 breast cancer models. Our results showed that the peptides and antibodies targeting residues 56-81 and 233-251 are potential therapeutic and vaccine candidates for the treatment of IGF-1R-expressing cancers, including those that are resistant to the HER-2-targeted antibody, trastuzumab. Additionally, we found additive antitumor effects for the combination treatment of the IGF-1R 56-81 epitope with HER-1-418 and HER-2-597 epitopes. Treatment with the IGF-1R/HER-1 or IGF-1R/HER-2 combination inhibited proliferation, invasion, and receptor phosphorylation, and induced apoptosis and ADCC, to a greater degree than single agents.
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Despite the tremendous efficacy of trastuzumab against HER2-overexpressing metastatic breast cancers, a significant fraction of women demonstrate progressive disease during treatment. Multiple mechanisms have been proposed to mediate trastuzumab resistance. In this mini-review, we discuss the evidence supporting FOXM1 as a mediator of resistance and potential new therapeutic target in trastuzumab-refractory breast cancer. FOXM1 expression is significantly elevated in multiple breast cancer data sets. Some studies suggest a direct correlation between FOXM1 and HER2 expression levels. In addition, overexpression of FOXM1 reduces the sensitivity of HER2-positive breast cancer cells to trastuzumab or lapatinib. Conversely, knockdown or pharmacological inhibition of FOXM1 rescues resistance to HER2-targeted therapies. Current pre-clinical information supports further investigation of the role of FOXM1 in trastuzumab-resistant breast cancer.