RESUMEN
Therapeutic resistance remains a major obstacle to successful clinical management of diffuse intrinsic pontine glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. On the basis of these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary studies demonstrated that micromolar levels of this inhibitor can be achieved in murine brain tissue and that MTX-241F exhibits promising single-agent efficacy and radiosensitizing activity in patient-derived DIPG neurospheres. Its physiochemical properties include high exposure in the brain, indicating excellent brain penetrance. Because radiotherapy results in double-strand breaks that are repaired by homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have tested the combination of MTX-241F with an inhibitor of Ataxia Telangiectasia Mutated to achieve blockade of HR and NHEJ, respectively, with or without radiotherapy. When HR blockers were combined with MTX-241F and radiotherapy, synthetic lethality was observed, providing impetus to explore this combination in clinically relevant models of DIPG. Our data provide proof-of-concept evidence to support advanced development of MTX-241F for the treatment of DIPG. Future studies will be designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease.
Asunto(s)
Neoplasias del Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Humanos , Niño , Ratones , Animales , Glioma Pontino Intrínseco Difuso/tratamiento farmacológico , Glioma Pontino Intrínseco Difuso/genética , Glioma Pontino Intrínseco Difuso/metabolismo , Recurrencia Local de Neoplasia , Reparación del ADN , Transducción de Señal , ADN/uso terapéutico , Neoplasias del Tronco Encefálico/tratamiento farmacológico , Neoplasias del Tronco Encefálico/genética , Neoplasias del Tronco Encefálico/patologíaRESUMEN
Despite tremendous progress in precision oncology, adaptive resistance mechanisms limit the long-term effectiveness of molecularly targeted agents. Here we evaluated the pharmacological profile of MTX-531 that was computationally designed to selectively target two key resistance drivers, epidermal growth factor receptor and phosphatidylinositol 3-OH kinase (PI3K). MTX-531 exhibits low-nanomolar potency against both targets with a high degree of specificity predicted by cocrystal structural analyses. MTX-531 monotherapy uniformly resulted in tumor regressions of squamous head and neck patient-derived xenograft (PDX) models. The combination of MTX-531 with mitogen-activated protein kinase kinase or KRAS-G12C inhibitors led to durable regressions of BRAF-mutant or KRAS-mutant colorectal cancer PDX models, resulting in striking increases in median survival. MTX-531 is exceptionally well tolerated in mice and uniquely does not lead to the hyperglycemia commonly seen with PI3K inhibitors. Here, we show that MTX-531 acts as a weak agonist of peroxisome proliferator-activated receptor-γ, an attribute that likely mitigates hyperglycemia induced by PI3K inhibition. This unique feature of MTX-531 confers a favorable therapeutic index not typically seen with PI3K inhibitors.
Asunto(s)
Resistencia a Antineoplásicos , Receptores ErbB , Inhibidores de Proteínas Quinasas , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Ratones , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Línea Celular Tumoral , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Femenino , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de Cabeza y Cuello/tratamiento farmacológicoRESUMEN
Neurofibromin 1 (NF1) loss of function (LoF) mutations are frequent in melanoma and drive hyperactivated RAS and tumor growth. NF1LoF melanoma cells, however, do not show consistent sensitivity to individual MEK, ERK, or PI3K/mTOR inhibitors. To identify more effective therapeutic strategies for treating NF1LoF melanoma, we performed a targeted kinase inhibitor screen. A tool compound named MTX-216 was highly effective in blocking NF1LoF melanoma growth in vitro and in vivo. Single-cell analysis indicated that drug-induced cytotoxicity was linked to effective cosuppression of proliferation marker Ki-67 and ribosomal protein S6 phosphorylation. The antitumor efficacy of MTX-216 was dependent on its ability to inhibit not only PI3K, its nominal target, but also SYK. MTX-216 suppressed expression of a group of genes that regulate mitochondrial electron transport chain and are associated with poor survival in patients with NF1LoF melanoma. Furthermore, combinations of inhibitors targeting either MEK or PI3K/mTOR with an independent SYK kinase inhibitor or SYK knockdown reduced the growth of NF1LoF melanoma cells. These studies provide a path to exploit SYK dependency to selectively target NF1LoF melanoma cells. SIGNIFICANCE: A kinase inhibitor screen identifies SYK as a targetable vulnerability in melanoma cells with NF1 loss of function.
Asunto(s)
Antineoplásicos , Melanoma , Humanos , Neurofibromina 1/genética , Quinasa Syk/genética , Quinasa Syk/uso terapéutico , Línea Celular Tumoral , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/farmacología , Quinasas de Proteína Quinasa Activadas por Mitógenos , Fosfatidilinositol 3-Quinasas/metabolismoRESUMEN
Significant advances in tumor sequencing have led to an explosion in our knowledge of the genetic complexity of cancer. For many cancers, the selection of a targetable alteration is not readily apparent, especially when confronted with mutational variants of unknown significance. The complex clinical landscape of MEK mutations illustrates the need for improved methods to identify those patients, independent of tumor histology, who would benefit from treatment with a MAP kinase pathway inhibitor. In this issue of Cancer Research, Hanrahan and colleagues adopt an in silico platform to attempt to distinguish benign MEK mutations from those that are functional and, therefore, most likely to be therapeutically actionable.See related article by Hanrahan et al., p. 4233.
Asunto(s)
Benchmarking , Neoplasias , Simulación por Computador , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos , Mutación , Neoplasias/genéticaRESUMEN
It has generally been assumed that MEK mutants function similarly to one another and respond in the same manner to targeted drugs. Gao and colleagues challenge this assumption and report that MEK1 mutants fall into three unique phenotypic classes with respect to RAF dependency. A new class of MEK1 mutants is shown here to be RAF-independent, resistant to allosteric MEK inhibitors, and yet sensitive to treatment with a new ATP-competitive MEK inhibitor. Cancer Discov; 8(5); 534-6. ©2018 AACRSee related article by Gao et al., p. 648.
Asunto(s)
Inhibidores de Proteínas Quinasas , Alelos , MAP Quinasa Quinasa 1/genéticaRESUMEN
A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesized using a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effect of variation in the carboxamide side chain, substitution on the pyridone nitrogen, and replacement of the 4'-iodide were all investigated. This study afforded several compounds which were either equipotent or more potent than the clinical candidate CI-1040 (1) in an isolated enzyme assay, as well as murine colon carcinoma (C26) cells, as measured by suppression of phosphorylated ERK substrate. Most notably, pyridone 27 was found to be more potent than 1 in vitro and produced a 100% response rate at a lower dose than 1, when tested for in vivo efficacy in animals bearing C26 tumors.
Asunto(s)
Amidas/síntesis química , Compuestos de Anilina/síntesis química , Antineoplásicos/síntesis química , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 2/antagonistas & inhibidores , Piridonas/síntesis química , Amidas/química , Amidas/farmacología , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Benzamidas/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , MAP Quinasa Quinasa 1/química , MAP Quinasa Quinasa 2/química , Masculino , Ratones , Modelos Moleculares , Trasplante de Neoplasias , Fosforilación , Piridonas/química , Piridonas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
We have recently synthesized a peptide called Disruptin, which comprised the SVDNPHVC segment of the epidermal growth factor receptor (EGFR) that inhibits binding of heat shock protein 90 (Hsp90) to the EGFR and EGF-dependent EGFR dimerization to cause EGFR degradation. The effect is specific for EGFR versus other Hsp90 client proteins [Ahsan et al.: (2013). Destabilization of the epidermal growth factor receptor (EGFR) by a peptide that inhibits EGFR binding to heat shock protein 90 and receptor dimerization. J Biol Chem288, 26879-26886]. Here, we show that Disruptin decreases the clonogenicity of a variety of EGFR-dependent cancer cells in culture but not of EGFR-independent cancer or noncancerous cells. The selectivity of Disruptin toward EGFR-driven cancer cells is due to the high level of EGF stimulation of EGFR in EGFR-dependent tumor cells relative to normal cells. When administered by intraperitoneal injection into nude mice bearing EGFR-driven human tumor xenografts, Disruptin causes extensive degradation of EGFR in the tumor but not in adjacent host tissue. Disruptin markedly inhibits the growth of EGFR-driven tumors without producing the major toxicities caused by the Hsp90 inhibitor geldanamycin or by cisplatin. These findings provide proof of concept for development of a new Disruptin-like class of antitumor drugs that are directed specifically against EGFR-driven tumors.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/farmacología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Fragmentos de Péptidos/farmacología , Animales , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Células CHO , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Cricetulus , Receptores ErbB/metabolismo , Receptores ErbB/uso terapéutico , Receptores ErbB/toxicidad , Femenino , Neoplasias de Cabeza y Cuello/patología , Humanos , Ratones Endogámicos C57BL , Ratones Desnudos , Fragmentos de Péptidos/uso terapéutico , Fragmentos de Péptidos/toxicidad , Proteolisis , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PNT100 is a 24-base, chemically unmodified DNA oligonucleotide sequence that is complementary to a region upstream of the BCL-2 gene. Exposure of tumor cells to PNT100 results in suppression of proliferation and cell death by a process called DNA interference. PNT2258 is PNT100 that is encapsulated in protective amphoteric liposomes developed to efficiently encapsulate the PNT100 oligonucleotide, provide enhanced serum stability, optimized pharmacokinetic properties and antitumor activity of the nanoparticle both in vivo and in vitro. PNT2258 demonstrates broad antitumor activity against BCL-2-driven WSU-DLCL2 lymphoma, highly resistant A375 melanoma, PC-3 prostate, and Daudi-Burkitt's lymphoma xenografts. The sequence specificity of PNT100 was demonstrated against three control sequences (scrambled, mismatched, and reverse complement) all encapsulated in a lipid formulation with identical particle characteristics, and control sequences did not demonstrate antiproliferative activity in vivo or in vitro. PNT2258 is currently undergoing clinical testing to evaluate safety and antitumor activity in patients with recurrent or refractory non-Hodgkin's lymphoma and additional studies are planned.