RESUMO
Estrogen receptor-positive (ER+) breast cancers frequently remain dependent on ER signaling even after acquiring resistance to endocrine agents, prompting the development of optimized ER antagonists. Fulvestrant is unique among approved ER therapeutics due to its capacity for full ER antagonism, thought to be achieved through ER degradation. The clinical potential of fulvestrant is limited by poor physicochemical features, spurring attempts to generate ER degraders with improved drug-like properties. We show that optimization of ER degradation does not guarantee full ER antagonism in breast cancer cells; ER "degraders" exhibit a spectrum of transcriptional activities and anti-proliferative potential. Mechanistically, we find that fulvestrant-like antagonists suppress ER transcriptional activity not by ER elimination, but by markedly slowing the intra-nuclear mobility of ER. Increased ER turnover occurs as a consequence of ER immobilization. These findings provide proof-of-concept that small molecule perturbation of transcription factor mobility may enable therapeutic targeting of this challenging target class.
Assuntos
Neoplasias da Mama/metabolismo , Antagonistas do Receptor de Estrogênio/farmacologia , Fulvestranto/farmacologia , Receptores de Estrogênio/antagonistas & inibidores , Receptores de Estrogênio/metabolismo , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Cinamatos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Antagonistas do Receptor de Estrogênio/uso terapêutico , Feminino , Fulvestranto/uso terapêutico , Células HEK293 , Xenoenxertos , Humanos , Indazóis/farmacologia , Ligantes , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Polimorfismo de Nucleotídeo Único , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacosRESUMO
BACKGROUND: HER2-positive, estrogen receptor-positive breast cancer (HER2+, ER+ BC) is a distinct disease subtype associated with inferior response to chemotherapy plus HER2-targeted therapy compared with HER2+, ER-negative BC. Bi-directional crosstalk leads to cooperation of the HER2 and ER pathways that may drive treatment resistance; thus, simultaneous co-targeting may optimize treatment impact and survival outcomes in patients with HER2+, ER+ BC. First-line (1L) treatment for patients with HER2+ metastatic BC (mBC) is pertuzumab, trastuzumab, and taxane chemotherapy. In clinical practice, dual HER2 blockade plus a fixed number of chemotherapy cycles are given as induction therapy to maximize tumor response, with subsequent HER2-targeted maintenance treatment given as a more tolerable regimen for long-term disease control. For patients whose tumors co-express ER, maintenance endocrine therapy (ET) can be added, but uptake varies due to lack of data from randomized clinical trials investigating the superiority of maintenance ET plus dual HER2 blockade versus dual HER2 blockade alone. Giredestrant, a novel oral selective ER antagonist and degrader, shows promising clinical activity and manageable safety across phase I-II trials of patients with ER+, HER2-negative BC, with therapeutic potential in those with HER2 co-expression. METHODS: This phase III, randomized, open-label, two-arm study aims to recruit 812 patients with HER2+, ER+ locally advanced (LA)/mBC into the induction phase (fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] plus a taxane) to enable 730 patients to be randomized 1:1 to the maintenance phase (giredestrant plus PH FDC SC or PH FDC SC [plus optional ET]), stratified by disease site (visceral versus non-visceral), type of LA/metastatic presentation (de novo versus recurrent), best overall response to induction therapy (partial/complete response versus stable disease), and intent to give ET (yes versus no). The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include overall survival, objective response rate, clinical benefit rate, duration of response, safety, and patient-reported outcomes. DISCUSSION: heredERA BC will address whether giredestrant plus dual HER2 blockade is superior to dual HER2 blockade alone, to inform the use of this combination in clinical practice for maintenance 1L treatment of patients with HER2+, ER+ LA/mBC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05296798; registered on March 25, 2022. Protocol version 3.0 (November 18, 2022). SPONSOR: F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124 4070, Basel, Switzerland.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Receptor ErbB-2 , Receptores de Estrogênio , Trastuzumab , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Injeções Subcutâneas , Metástase Neoplásica , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Trastuzumab/administração & dosagem , Trastuzumab/uso terapêuticoRESUMO
Colorectal cancer remains a major unmet medical need, prompting large-scale genomics efforts in the field to identify molecular drivers for which targeted therapies might be developed. We previously reported the identification of recurrent translocations in R-spondin genes present in a subset of colorectal tumours. Here we show that targeting RSPO3 in PTPRK-RSPO3-fusion-positive human tumour xenografts inhibits tumour growth and promotes differentiation. Notably, genes expressed in the stem-cell compartment of the intestine were among those most sensitive to anti-RSPO3 treatment. This observation, combined with functional assays, suggests that a stem-cell compartment drives PTPRK-RSPO3 colorectal tumour growth and indicates that the therapeutic targeting of stem-cell properties within tumours may be a clinically relevant approach for the treatment of colorectal tumours.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Terapia de Alvo Molecular , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Trombospondinas/metabolismo , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Divisão Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Progressão da Doença , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mucosa Intestinal/metabolismo , Intestinos/citologia , Intestinos/efeitos dos fármacos , Intestinos/patologia , Masculino , Camundongos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Trombospondinas/antagonistas & inibidores , Trombospondinas/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Estrogen Receptor alpha (ERα) stands as one of the most successfully prosecuted drug targets in oncology, beginning with the approval of tamoxifen for women with ERα positive (ER+) breast cancer over 40 years ago. The field continued to advance with the development of aromatase inhibitors and the pure antiestrogen fulvestrant. With multiple endocrine therapies approved for the treatment of ER+ breast cancer, efforts to generate novel ERα-targeted therapeutics somewhat diminished in the early 2000s. Today however, there are at least eight new molecular entities targeting ERα under active clinical investigation, each with the aim of bringing further benefit to patients. This remarkable re-energizing of the field was spurred in part by the discovery of highly prevalent ERα mutations as a mechanism of resistance to standard-of-care therapies, which provided unequivocal evidence of the continued, and broad, dependence of tumors on ERα, despite relapsing after earlier lines of endocrine therapy. Re-engagement of the pharmaceutical and biotechnology industries with ERα as a drug target has been further underpinned by the impressive advances made in medicinal chemistry, enabling desirable mechanistic features - high potency full ERα antagonism - to be combined with improved drug-like properties - oral bioavailability and optimized pharmacokinetics. In this chapter, we describe the rich history and science behind the currently evolving landscape of ERα targeting in breast cancer.
Assuntos
Neoplasias da Mama , Receptores de Estrogênio , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Estradiol/farmacologia , Moduladores de Receptor Estrogênico/uso terapêutico , Receptor alfa de Estrogênio/genética , Feminino , Fulvestranto/uso terapêutico , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Receptores de Estrogênio/genética , Tamoxifeno/uso terapêuticoRESUMO
Fulvestrant is an FDA-approved drug with a dual mechanism of action (MOA), acting as a full antagonist and degrader of the estrogen receptor protein. A significant limitation of fulvestrant is the dosing regimen required for efficacy. Due to its high lipophilicity and poor pharmacokinetic profile, fulvestrant needs to be administered through intramuscular injections which leads to injection site soreness. This route of administration also limits the dose and target occupancy in patients. We envisioned a best-in-class molecule that would function with the same dual MOA as fulvestrant, but with improved physicochemical properties and would be orally bioavailable. Herein we report our progress toward that goal, resulting in a new lead GNE-502 which addressed some of the liabilities of our previously reported lead molecule GNE-149.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Descoberta de Drogas , Receptores de Estrogênio/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Relação Dose-Resposta a Droga , Feminino , Humanos , Células MCF-7 , Camundongos , Estrutura Molecular , Conformação Proteica , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND & AIMS: Indian hedgehog (IHH) is an epithelial-derived signal in the intestinal stroma, inducing factors that restrict epithelial proliferation and suppress activation of the immune system. In addition to these rapid effects of IHH signaling, IHH is required to maintain a stromal phenotype in which myofibroblasts and smooth muscle cells predominate. We investigated the role of IHH signaling during development of intestinal neoplasia in mice. METHODS: Glioma-associated oncogene (Gli1)-CreERT2 and Patched (Ptch)-lacZ reporter mice were crossed with Apc(Min) mice to generate Gli1CreERT2-Rosa26-ZSGreen-Apc(Min) and Ptch-lacZ-Apc(Min) mice, which were used to identify hedgehog-responsive cells. Cyp1a1Cre-Apc (Apc(HET)) mice, which develop adenomas after administration of ß-naphthoflavone, were crossed with mice with conditional disruption of Ihh in the small intestine epithelium. Apc(Min) mice were crossed with mice in which sonic hedgehog (SHH) was overexpressed specifically in the intestinal epithelium. Intestinal tissues were collected and analyzed histologically and by immunohistochemistry and quantitative reverse-transcription polymerase chain reaction. We also analyzed levels of IHH messenger RNA and expression of IHH gene targets in intestinal tissues from patients with familial adenomatous polyposis (n = 18) or sessile serrated adenomas (n = 15) and normal colonic tissue from control patients (n = 12). RESULTS: Expression of IHH messenger RNA and its targets were increased in intestinal adenomas from patients and mice compared with control colon tissues. In mice, IHH signaling was exclusively paracrine, from the epithelium to the stroma. Loss of IHH from Apc(HET) mice almost completely blocked adenoma development, and overexpression of SHH increased the number and size of adenomas that developed. Loss of IHH from Apc(HET) mice changed the composition of the adenoma stroma; cells that expressed α-smooth muscle actin or desmin were lost, along with expression of cyclooxygenase-2, and the number of vimentin-positive cells increased. CONCLUSIONS: Apc mutant epithelial cells secrete IHH to maintain an intestinal stromal phenotype that is required for adenoma development in mice.
Assuntos
Adenoma/metabolismo , Biomarcadores Tumorais/metabolismo , Transformação Celular Neoplásica/metabolismo , Proteínas Hedgehog/metabolismo , Neoplasias Intestinais/metabolismo , Transdução de Sinais , Células Estromais/metabolismo , Adenoma/induzido quimicamente , Adenoma/genética , Adenoma/patologia , Polipose Adenomatosa do Colo/metabolismo , Polipose Adenomatosa do Colo/patologia , Animais , Comunicação Autócrina , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Citocromo P-450 CYP1A1/genética , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica , Genes APC , Predisposição Genética para Doença , Proteínas Hedgehog/genética , Humanos , Hiperplasia , Integrases/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Neoplasias Intestinais/induzido quimicamente , Neoplasias Intestinais/genética , Neoplasias Intestinais/patologia , Camundongos Transgênicos , Mutação , Comunicação Parácrina , Fenótipo , RNA Mensageiro/metabolismo , Células Estromais/patologia , Carga Tumoral , beta-NaftoflavonaRESUMO
As CDK4/6 inhibitor (CDK4/6i) approval changed treatment strategies for patients with hormone receptor-positive HER2-negative (HR+/HER2-) breast cancer (BC), understanding how exposure to CDK4/6i affects the tumor genomic landscape is critical for precision oncology. Using real-world data (RWD) with tumor genomic profiling from 5910 patients with metastatic HR+/HER2- BC, we investigated the evolution of alteration prevalence in commonly mutated genes across patient journeys. We found that ESR1 is more often altered in tumors exposed to at least 1 year of adjuvant endocrine therapy, contrasting with TP53 alterations. We observed a similar trend after first-line treatments in the advanced setting, but strikingly exposure to aromatase inhibitors (AI) combined with CDK4/6i led to significantly higher ESR1 alteration prevalence compared to AI alone, independent of treatment duration. Further, CDK4/6i exposure was associated with higher occurrence of concomitant alterations in multiple oncogenic pathways. Differences based on CDK4/6i exposure were confirmed in samples collected after 2L and validated in samples from the acelERA BC clinical trial. In conclusion, our work uncovers opportunities for further treatment personalization and stresses the need for effective combination treatments to address the altered tumor genomic landscape following AI+CDK4/6i exposure. Further, we demonstrated the potential of RWD for refining patient treatment strategy and guiding clinical trial design.
RESUMO
The key read-out of Wnt signalling is a change in the transcriptional profile of the cell, which is driven by ß-catenin. ß-catenin levels are normally kept low by a phosphorylation event that is mediated by glycogen synthase kinase 3 (GSK3, α- and ß-isoforms), which targets ß-catenin for ubiquitylation and proteasomal degradation. Wnt blocks this phosphorylation event, thereby allowing ß-catenin to accumulate and to co-activate transcription in the nucleus. Exactly how Wnt inhibits GSK3 activity towards ß-catenin is unclear and has been the focus of intensive research. Recent studies on the role of conserved PPPSPxS motifs in the cytoplasmic tail of low-density lipoprotein receptor-related protein (LRP, isoforms 5 and 6) culminated in a biochemical model: Wnt induces the phosphorylation of LRP6 PPPSPxS motifs, which consequently access the catalytic pocket of GSK3 as pseudo-substrates, thus directly blocking its activity against ß-catenin. A distinct cell-biological model was proposed more recently: Wnt proteins induce the uptake of GSK3 into multivesicular bodies (MVBs), an event that sequesters the enzyme away from newly synthesised ß-catenin substrate in the cytoplasm, thus blocking its phosphorylation. This new model is based on intriguing observations but also challenges a body of existing evidence, so will require further experimental consolidation. We shall consider whether the two models apply to different modes of Wnt signaling: acute versus chronic.
Assuntos
Regulação para Baixo , Quinase 3 da Glicogênio Sintase/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/genética , Humanos , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Modelos Biológicos , Corpos Multivesiculares/genética , Corpos Multivesiculares/metabolismo , Fosforilação , Proteínas Wnt/genética , beta Catenina/genéticaRESUMO
The hormone receptor oestrogen receptor-α (ER) orchestrates physiological mammary gland development, breast carcinogenesis and the progression of breast tumours into lethal, treatment-refractory systemic disease. Selective antagonism of ER signalling has been one of the most successful therapeutic approaches in oncology, benefiting patients as both a cancer preventative measure and a cancer treatment strategy. However, resistance to anti-oestrogen therapy is a major clinical challenge. Over the past decade, we have gained an understanding of how breast cancers evolve under the pressure of anti-oestrogen therapy. This is best depicted by the case of oestrogen-independent mutations in the gene encoding ER (ESR1), which are virtually absent in primary breast cancer but highly prevalent (20-40%) in anti-oestrogen-treated metastatic disease. These and other findings highlight the 'evolvability' of ER+ breast cancer and the need to understand molecular processes by which this evolution occurs. Recent development and approval of next-generation ER antagonists to target ESR1-mutant breast cancer underscores the clinical importance of this evolvability and sets a new paradigm for the treatment of ER+ breast cancers.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Estrogênios , Transdução de SinaisRESUMO
Self-renewal and differentiation of stem and progenitor cells are tightly regulated to ensure tissue homeostasis. This regulation is enabled both remotely by systemic circulating cues, such as cytokines and hormones, and locally by various niche-confined factors. R-spondin 3 (RSPO3) is one of the most potent enhancers of Wnt signaling, and its expression is usually restricted to the stem cell niche where it provides localized enhancement of Wnt signaling to regulate stem cell expansion and differentiation. Disruption of this niche-confined expression can disturb proper tissue organization and lead to cancers. Here, we investigate the consequences of disrupting the niche-restricted expression of RSPO3 in various tissues, including the hematopoietic system. We show that normal Rspo3 expression is confined to the perivascular niche in the bone marrow. Induction of increased systemic levels of circulating RSPO3 outside of the niche results in prominent loss of early B-cell progenitors and anemia but surprisingly has no effect on hematopoietic stem cells. Using molecular, pharmacologic, and genetic approaches, we show that these RSPO3-induced hematopoietic phenotypes are Wnt and RSPO3 dependent and mediated through noncanonical Wnt signaling. Our study highlights a distinct role for a Wnt/RSPO3 signaling axis in the regulation of hematopoiesis, as well as possible challenges related to therapeutic use of RSPOs for regenerative medicine.
Assuntos
Hematopoese , Nicho de Células-Tronco , Hematopoese/genética , Células-Tronco Hematopoéticas , Diferenciação Celular/genética , Via de Sinalização Wnt/fisiologiaRESUMO
PURPOSE: GDC-0927 is a novel, potent, nonsteroidal, orally bioavailable, selective estrogen receptor (ER) degrader that induces tumor regression in ER+ breast cancer xenograft models. PATIENTS AND METHODS: This phase I dose-escalation multicenter study enrolled postmenopausal women with ER+/HER2- metastatic breast cancer to determine the safety, pharmacokinetics, and recommended phase II dose of GDC-0927. Pharmacodynamics was assessed with [18F]-fluoroestradiol (FES) PET scans. RESULTS: Forty-two patients received GDC-0927 once daily. The MTD was not reached. The most common adverse events (AE) regardless of causality were nausea, constipation, diarrhea, arthralgia, fatigue, hot flush, back pain, and vomiting. There were no deaths, grade 4/5 AEs, or treatment-related serious AEs. Two patients experienced grade 2 AEs of special interest of deep vein thrombosis and jugular vein thrombosis, both considered unrelated to GDC-0927. Following dosing, approximately 1.6-fold accumulation was observed, consistent with the observed half-life and dosing frequency. There were no complete or partial responses. Pharmacodynamics was supported by >90% reduction in FES uptake and an approximately 40% reduction in ER expression, suggesting ER degradation is not the mechanistic driver of ER antagonism. Twelve patients (29%) achieved clinical benefit; 17 patients (41%) showed a confirmed best overall response of stable disease. Baseline levels of ER and progesterone receptor protein and mutant ESR1 circulating tumor DNA did not correlate with clinical benefit. CONCLUSIONS: GDC-0927 appeared to be well tolerated with pharmacokinetics supporting once-daily dosing. There was evidence of target engagement and preliminary evidence of antitumor activity in heavily pretreated patients with advanced/metastatic ER+/HER2- breast cancer with and without ESR1 mutations.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptores de Estrogênio/genética , Pós-Menopausa , Antagonistas do Receptor de Estrogênio , Tomografia por Emissão de PósitronsRESUMO
Wnt/beta-catenin signalling controls cell fates in development, tissue homeostasis and cancer. Wnt binding to Frizzled receptors triggers recruitment of Dishevelled to the plasma membrane and formation of a signalosome containing the LRP5/6 co-receptor, whose cytoplasmic tail (ctail) thus becomes phosphorylated at multiple PPP(S/T)Px(S/T) motifs. These then directly inhibit GSK3beta, which results in beta-catenin accumulation and signalling. Here, we revisit previous epistasis experiments, and show that Dishevelled signals through LRP5/6 in human cells and Drosophila embryos. To recapitulate this signalling event, and to define its functional elements, we fused the Dishevelled DIX domain to the LRP6 ctail, which forms cytoplasmic signalosomes with potent signalling activity mediated by its PPP(S/T)Px(S/T) motifs. Their phosphorylation and activity depends critically on DIX-mediated polymerization, and on multiple stability elements in the LRP6 ctail, including the T1479 epitope upstream of the membrane-proximal PPP(S/T)Px(S/T) motif. Thus, stable polymerization emerges as a key principle underlying the function of Dishevelled-dependent signalosomes.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/química , Biopolímeros/metabolismo , Drosophila melanogaster/metabolismo , Fosfoproteínas/química , Estabilidade Proteica , Receptores de LDL/química , Receptores de LDL/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Proteína Axina , Linhagem Celular , Proteínas Desgrenhadas , Proteínas de Drosophila/química , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriologia , Embrião não Mamífero/metabolismo , Epitopos/química , Humanos , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Dados de Sequência Molecular , Fosfoproteínas/metabolismo , Fosforilação , Estrutura Terciária de Proteína , Receptores de Superfície Celular/química , Receptores de Superfície Celular/metabolismo , Proteínas Repressoras/metabolismo , Relação Estrutura-Atividade , Proteínas Wnt/metabolismoRESUMO
INTRODUCTION: The selective estrogen receptor degrader (SERD) and full receptor antagonist provides an important therapeutic option for hormone receptor (HR)-positive breast cancer. Endocrine therapies include tamoxifen, a selective estrogen receptor modulator (SERM), that exhibits receptor agonist and antagonist activity, and aromatase inhibitors that block estrogen biosynthesis but which demonstrate acquired resistance. Fulvestrant, the only currently approved SERD, is limited by poor drug-like properties. A key focus for improving disease management has been development of oral SERDs with optimized target occupancy and potency and superior clinical efficacy. AREAS COVERED: Using PubMed, clinicaltrials.gov, and congress websites, this review explored the preclinical development and clinical pharmacokinetics from early phase clinical studies (2015 or later) of novel oral SERDs, including giredestrant, amcenestrant, camizestrant, elacestrant, and rintodestrant. EXPERT OPINION: Numerous oral SERDs are in clinical development, aiming to form the core endocrine therapy for HR-positive breast cancer. Through property- and structure-based drug design of estrogen receptor-binding, antagonism, degradation, anti-proliferation, and pharmacokinetic properties, these SERDs have distinct profiles which impact clinical dosing, efficacy, and safety. Assuming preliminary safety and activity data are confirmed in phase 3 trials, these promising agents could further improve the management, outcomes, and quality of life in HR-positive breast cancer.
Assuntos
Neoplasias da Mama , Receptores de Estrogênio , Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/farmacologia , Antagonistas de Estrogênios/uso terapêutico , Feminino , Fulvestranto/farmacocinética , Fulvestranto/uso terapêutico , Humanos , Qualidade de Vida , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/efeitos adversosRESUMO
ESR1 (estrogen receptor 1) hotspot mutations are major contributors to therapeutic resistance in estrogen receptor-positive (ER+) breast cancer. Such mutations confer estrogen independence to ERα, providing a selective advantage in the presence of estrogen-depleting aromatase inhibitors. In addition, ESR1 mutations reduce the potency of tamoxifen and fulvestrant, therapies that bind ERα directly. These limitations, together with additional liabilities, inspired the development of the next generation of ERα-targeted therapeutics, of which giredestrant is a high-potential candidate. Here, we generated Esr1 mutant-expressing mammary gland models and leveraged patient-derived xenografts (PDXs) to investigate the biological properties of the ESR1 mutations and their sensitivity to giredestrant in vivo. In the mouse mammary gland, Esr1 mutations promote hypersensitivity to progesterone, triggering pregnancy-like tissue remodeling and profoundly elevated proliferation. These effects were driven by an altered progesterone transcriptional response and underpinned by gained sites of ERα-PR (progesterone receptor) cobinding at the promoter regions of pro-proliferation genes. PDX experiments showed that the mutant ERα-PR proliferative program is also relevant in human cancer cells. Giredestrant suppressed the mutant ERα-PR proliferation in the mammary gland more so than the standard-of-care agents, tamoxifen and fulvestrant. Giredestrant was also efficacious against the progesterone-stimulated growth of ESR1 mutant PDX models. In addition, giredestrant demonstrated activity against a molecularly characterized ESR1 mutant tumor from a patient enrolled in a phase 1 clinical trial. Together, these data suggest that mutant ERα can collaborate with PR to drive protumorigenic proliferation but remain sensitive to inhibition by giredestrant.
Assuntos
Neoplasias da Mama , Receptor alfa de Estrogênio , Animais , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carbolinas , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Estrogênios , Feminino , Fulvestranto/farmacologia , Fulvestranto/uso terapêutico , Humanos , Camundongos , Mutação/genética , Progesterona/farmacologia , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Receptores de Progesterona/uso terapêutico , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêuticoRESUMO
Breast cancer is now globally the most frequent cancer and leading cause of women's death. Two thirds of breast cancers express the luminal estrogen receptor-positive (ERα + ) phenotype that is initially responsive to antihormonal therapies, but drug resistance emerges. A major barrier to the understanding of the ERα-pathway biology and therapeutic discoveries is the restricted repertoire of luminal ERα + breast cancer models. The ERα + phenotype is not stable in cultured cells for reasons not fully understood. We examine 400 patient-derived breast epithelial and breast cancer explant cultures (PDECs) grown in various three-dimensional matrix scaffolds, finding that ERα is primarily regulated by the matrix stiffness. Matrix stiffness upregulates the ERα signaling via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation. The finding that the matrix stiffness is a central cue to the ERα phenotype reveals a mechanobiological component in breast tissue hormonal signaling and enables the development of novel therapeutic interventions. Subject terms: ER-positive (ER + ), breast cancer, ex vivo model, preclinical model, PDEC, stiffness, p38 SAPK.
Assuntos
Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Mecanotransdução Celular/genética , Transcriptoma , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Cinamatos/farmacologia , Colágeno/química , Colágeno/farmacologia , Combinação de Medicamentos , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Fulvestranto/farmacologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Histonas/genética , Histonas/metabolismo , Humanos , Indazóis/farmacologia , Laminina/química , Laminina/farmacologia , Glândulas Mamárias Humanas/efeitos dos fármacos , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , Fenótipo , Proteoglicanas/química , Proteoglicanas/farmacologia , Tamoxifeno/farmacologia , Técnicas de Cultura de Tecidos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Breast cancer remains a leading cause of cancer death in women, representing a significant unmet medical need. Here, we disclose our discovery efforts culminating in a clinical candidate, 35 (GDC-9545 or giredestrant). 35 is an efficient and potent selective estrogen receptor degrader (SERD) and a full antagonist, which translates into better antiproliferation activity than known SERDs (1, 6, 7, and 9) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing of 35 in preclinical species and humans. 35 exhibits low drug-drug interaction liability and demonstrates excellent in vitro and in vivo safety profiles. At low doses, 35 induces tumor regressions either as a single agent or in combination with a CDK4/6 inhibitor in an ESR1Y537S mutant PDX or a wild-type ERα tumor model. Currently, 35 is being evaluated in Phase III clinical trials.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carbolinas/uso terapêutico , Antagonistas do Receptor de Estrogênio/uso terapêutico , Receptor alfa de Estrogênio/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Carbolinas/química , Carbolinas/farmacocinética , Cães , Antagonistas do Receptor de Estrogênio/química , Antagonistas do Receptor de Estrogênio/farmacocinética , Feminino , Humanos , Células MCF-7 , Macaca fascicularis , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The PI3K signaling pathway serves as a central node in regulating cell survival, proliferation, and metabolism. PIK3CA, the gene encoding the PI3K catalytic subunit p110-alpha, is commonly altered in breast cancer resulting in the constitutive activation of the PI3K pathway. Using an unbiased cell line screening approach, we tested the sensitivity of breast cancer cell lines to taselisib, a potent PI3K inhibitor, and correlated sensitivity with key biomarkers (PIK3CA, HER2, PTEN, and ESR1). We further assessed how taselisib modulates downstream signaling in the different genomic backgrounds that occur within breast cancer. We found that sensitivity to taselisib correlated with the presence of PIK3CA mutations, but was independent of HER2 status. We further showed that HER2-amplified/PIK3CA wild-type cell lines are not as sensitive to taselisib when compared with HER2-amplified/PIK3CA-mutant cell lines. In a PIK3CA-mutant/PTEN null background, PI3K downstream signaling rebounded in the presence of taselisib correlating with decreased sensitivity at later time points. Finally, we observed that PIK3CA mutations cooccurred with mutations in the estrogen receptor (ER; ESR1) in metastatic tumors from patients with ER+ breast cancer. However, the cooccurrence of an ESR1 mutation with a PIK3CA mutation did not affect response to taselisib in a single agent setting or in combination with fulvestrant. In summary, these data suggest that development of taselisib in breast cancer should occur in a PIK3CA-mutant setting with cotreatments determined by the specific subtypes under investigation.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores/metabolismo , Neoplasias da Mama/tratamento farmacológico , Imidazóis/uso terapêutico , Oxazepinas/uso terapêutico , Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Imidazóis/farmacologia , Oxazepinas/farmacologiaRESUMO
Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer. Fulvestrant is FDA-approved to treat ER+ breast cancer and works through two mechanisms-as a full antagonist and selective estrogen receptor degrader (SERD)-but lacks oral bioavailability. Thus, we envisioned a "best-in-class" molecule with the same dual mechanisms as fulvestrant, but with significant oral exposure. Through lead optimization, we discovered a tool molecule 12 (GNE-149) with improved degradation and antiproliferative activity in both MCF7 and T47D cells. To illustrate the binding mode and key interactions of this scaffold with ERα, we obtained a cocrystal structure of 6 that showed ionic interaction of azetidine with Asp351 residue. Importantly, 12 showed favorable metabolic stability and good oral exposure. 12 exhibited antagonist effect in the uterus and demonstrated robust dose-dependent efficacy in xenograft models.
RESUMO
ER-targeted therapeutics provide valuable treatment options for patients with ER+ breast cancer, however, current relapse and mortality rates emphasize the need for improved therapeutic strategies. The recent discovery of prevalent ESR1 mutations in relapsed tumors underscores a sustained reliance of advanced tumors on ERα signaling, and provides a strong rationale for continued targeting of ERα. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ERα degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ERα conformation, relative to that induced by currently approved therapeutics, suggesting a unique mechanism of action. GDC-0810 has robust in vitro and in vivo activity against a variety of human breast cancer cell lines and patient derived xenografts, including a tamoxifen-resistant model and those that harbor ERα mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Cinamatos/administração & dosagem , Indazóis/administração & dosagem , Receptores de Estrogênio/administração & dosagem , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Xenoenxertos , Humanos , Camundongos , Estudos Prospectivos , Ratos , Resultado do TratamentoRESUMO
The adult lung is largely quiescent, with airway epithelia turning over slowly. Peng et al. (2015) describe a key role for the Hedgehog pathway in actively maintaining this quiescence, a surprising turn of events given the pathway's established mitogenic role, and they show that Hedgehog pathway attenuation is required for proliferative regeneration.