scholarly journals Combining Targeted Therapy With Immunotherapy in BRAF-Mutant Melanoma: Promise and Challenges

2014 ◽  
Vol 32 (21) ◽  
pp. 2248-2254 ◽  
Author(s):  
Siwen Hu-Lieskovan ◽  
Lidia Robert ◽  
Blanca Homet Moreno ◽  
Antoni Ribas
Keyword(s):  
Targeted Therapy ◽  
Braf Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Braf Inhibitors ◽  
Oncogenic Signaling ◽  
Pathway Activation ◽  
Prolonged Duration ◽  
Trial Testing ◽  
Mitogen Activated Protein ◽  
Braf Mutant

Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer. Targeted therapy can successfully block oncogenic signaling in BRAFV600-mutant melanoma with high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma. These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAFV600 driver mutation in the tumor cells and potentially sensitize the immune system to target tumors. However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non–BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Here, we present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials.

scholarly journals Successful Use of BRAF/MEK Inhibitors as a Neoadjuvant Approach in the Definitive Treatment of Papillary Craniopharyngioma

2020 ◽  
Vol 18 (12) ◽  
pp. 1590-1595
Author(s):  
Karam Khaddour ◽  
Michael R. Chicoine ◽  
Jiayi Huang ◽  
Sonika Dahiya ◽  
George Ansstas
Keyword(s):  
Targeted Therapy ◽  
Kinase Inhibitor ◽  
Case Reports ◽  
Braf Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Definitive Treatment ◽  
High Morbidity ◽  
Who Grade ◽  
Suprasellar Region ◽  
Mitogen Activated Protein

Craniopharyngiomas are rare tumors that arise in the suprasellar region of the brain and are known for their aggressive nature despite their WHO grade I. This is due to the complex neuroanatomy of the sellar/suprasellar region and their proximity to the optic nerve apparatus, hypothalamic–pituitary tract, and other critical neuroanatomical structures. Definitive treatment is based on a multidisciplinary approach and often involves a combination of surgical, radiation, and medical therapy. However, there is high morbidity associated with surgery and RT due to the complex neuroanatomy of this region. Recently, BRAFV600E somatic mutation has been identified in most papillary craniopharyngiomas. This discovery has led to the novel use of RAF pathway inhibitors to treat these tumors. We report the successful use of dabrafenib (BRAF inhibitor) and trametinib (mitogen-activated protein kinase kinase inhibitor) in the neoadjuvant setting followed by definitive stereotactic radiosurgery. We propose an algorithm based on available literature on the integration of targeted therapy in the management of papillary craniopharyngiomas. Our observations, together with prior case reports, advocate the incorporation of targeted therapy for unresectable craniopharyngiomas and reinforce that treatment with dual-targeted therapy is safe and effective.

scholarly journals PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Antoni Ribas ◽  
Alain Algazi ◽  
Paolo A. Ascierto ◽  
Marcus O. Butler ◽  
Sunandana Chandra ◽  
...  
Keyword(s):  
Phase 1 ◽  
Treatment Options ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Advanced Melanoma ◽  
Mitogen Activated Protein Kinase ◽  
Oncogenic Signaling ◽  
Open Label ◽  
Mitogen Activated Protein

AbstractCombining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti–PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti–PD-L1 therapy may provide treatment options for patients with advanced melanoma.

scholarly journals Targeted Therapy for Colorectal Cancers With Non-V600 BRAF Mutations: Perspectives for Precision Oncology

2018 ◽  
pp. 1-12 ◽  
Author(s):  
Matthew Dankner
Keyword(s):  
Targeted Therapy ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Colorectal Cancers ◽  
Precision Oncology ◽  
Braf Mutations ◽  
Egfr Inhibition ◽  
Mitogen Activated Protein ◽  
Braf Mutant ◽  
Kinase Pathway

BRAF mutations are found in up to 10% of colorectal cancers (CRC). Whereas the majority of BRAF mutant CRCs harbor V600 mutations, up to 25% express non-V600 BRAF mutations. It has been established that BRAF V600E mutations in CRC predict unresponsiveness to epidermal growth factor receptor (EGFR) inhibition—cetuximab and/or panitumumab—as a result of the constitutive activation of the mitogen-activated protein kinase pathway downstream of EGFR signaling. As more centers begin using next-generation sequencing assays to detect BRAF mutations, oncologists are more frequently confronted with treating patients with non-V600 BRAF mutations. In many instances, clinicians may be hesitant to use EGFR inhibitors for these patients, as it is largely assumed that tumors with non-V600 BRAF mutations activate the mitogen-activated protein kinase pathway in a similar manner to RAS or BRAF V600E mutations and would therefore be equally refractory to EGFR inhibition; however, the evidence that currently exists to substantiate this claim is mixed and incomplete. Recent data demonstrate that non-V600 BRAF mutant CRC is a distinct clinical entity with a favorable prognosis compared with CRC with V600E mutations. Preclinical data and several case reports suggest that a subset of BRAF non-V600 mutations that impair the protein's kinase activity may in fact confer heightened sensitivity to EGFR inhibition because of dependency on upstream receptor tyrosine kinase signaling. This review summarizes the clinical characteristics and targeted therapy approaches for non-V600 BRAF mutant CRCs, speculates on the value of non-V600 BRAF mutations as predictive biomarkers of responsiveness to EGFR inhibitors, and highlights outstanding questions in this emerging area of precision oncology.

Adaphostin promotes caffeine-evoked autocrine Fas-mediated death pathway activation in Bcr/Abl-positive leukaemia cells

2011 ◽  
Vol 439 (3) ◽  
pp. 453-470 ◽  
Author(s):  
Wen-Hsin Liu ◽  
Long-Sen Chang
Keyword(s):  
P38 Mapk ◽  
K562 Cells ◽  
Mitogen Activated Protein Kinase ◽  
Pathway Activation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
P38α Mapk ◽  
Activating Transcription Factor ◽  
Leukaemia Therapy ◽  
Jnk Activation

The present study was conducted to verify whether caffeine is beneficial for improving leukaemia therapy. Co-treatment with adaphostin (a Bcr/Abl inhibitor) was found to potentiate caffeine-induced Fas/FasL up-regulation. Although adaphostin did not elicit ASK1 (apoptosis signal-regulating kinase 1)-mediated phosphorylation of p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase), co-treatment with adaphostin notably increased p38 MAPK/JNK activation in caffeine-treated cells. Suppression of p38 MAPK and JNK abrogated Fas/FasL up-regulation in caffeine- and caffeine/adaphostin-treated cells. Compared with caffeine, adaphostin markedly suppressed Akt/ERK (extracellular-signal-regulated kinase)-mediated MKP-1 (MAPK phosphatase 1) protein expression in K562 cells. MKP-1 down-regulation eventually elucidated the enhanced effect of adaphostin on p38 MAPK/JNK activation and subsequent Fas/FasL up-regulation in caffeine-treated cells. Knockdown of p38α MAPK and JNK1, ATF-2 (activating transcription factor 2) and c-Jun by siRNA (small interfering RNA) proved that p38α MAPK/ATF-2 and JNK1/c-Jun pathways were responsible for caffeine-evoked Fas/FasL up-regulation. Moreover, Ca2+ and ROS (reactive oxygen species) were demonstrated to be responsible for ASK1 activation and Akt/ERK inactivation respectively in caffeine- and caffeine/adaphostin-treated cells. Likewise, adaphostin functionally enhanced caffeine-induced Fas/FasL up-regulation in leukaemia cells that expressed Bcr/Abl. Taken together, the results of the present study suggest a therapeutic strategy in improving the efficacy of adaphostin via Fas-mediated death pathway activation in Bcr/Abl-positive leukaemia.

Claudin-1 is linked to presence of implants and micropapillary pattern in serous borderline epithelial tumours of the ovary

2018 ◽  
Vol 71 (12) ◽  
pp. 1060-1064 ◽  
Author(s):  
Ahmed El-Balat ◽  
Iryna Schmeil ◽  
Khayal Gasimli ◽  
Nicole Sänger ◽  
Thomas Karn ◽  
...  
Keyword(s):  
Figo Stage ◽  
Mitogen Activated Protein Kinase ◽  
Borderline Tumour ◽  
Peritoneal Implants ◽  
Gynecology And Obstetrics ◽  
Pathway Activation ◽  
Therapeutic Value ◽  
Mitogen Activated Protein ◽  
Epithelial Tumours ◽  
Micropapillary Pattern

AimsExpression of Claudin-1 has been associated with prognosis in several cancers. Here we investigated the expression pattern of Claudin-1 in borderline tumours of the ovary (BOT).MethodsWe analysed a cohort of 114 cases of borderline tumour (BOT). Claudin-1 expression was studied by immunohistochemistry using a polyclonal antibody and was compared with clinical and histopathological characteristics.ResultsStrong Claudin-1 expression was found in 30 cases (26.3%) independent of histological subtype. Expression was significantly less frequent in International Federation of Gynecology and Obstetrics (FIGO) stage I (p= 0.045), while the presence of microinvasion did not correlate with Claudin-1 expression. In contrast, we detected a highly significant association of Claudin-1 expression with the presence of peritoneal implants (p=0.003) and micropapillary pattern (p=0.047), which are features exclusively seen in serous BOT. Moreover, when we restricted our analysis to the subtype of serous BOT, the association of Claudin-1 expression with peritoneal implants (p<0.001) and micropapillary pattern (p =0.003) remained highly significant.ConclusionsIn conclusion, Claudin-1 expression is associated with the presence of peritoneal implants and micropapillary pattern, which have been shown to be associated with poor prognosis. We speculate that overexpression of Claudin-1 might be linked to the mitogen-activated protein kinase pathway activation in BOT and suggest further studies to define its prognostic and potential therapeutic value.

Polymorphous Low-Grade Neuroepithelial Tumor of the Young (PLNTY): Molecular Profiling Confirms Frequent MAPK Pathway Activation

2021 ◽  
Author(s):  
Cristiane M Ida ◽  
Derek R Johnson ◽  
Asha A Nair ◽  
Jaime Davila ◽  
Thomas M Kollmeyer ◽  
...  
Keyword(s):  
Copy Number ◽  
Mapk Pathway ◽  
Braf V600e Mutation ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Low Grade ◽  
Pathway Activation ◽  
Mitogen Activated Protein ◽  
Copy Number Changes ◽  
Cd34 Expression

Abstract Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and frequent mitogen-activated protein kinase (MAPK) pathway activation. We molecularly profiled 13 cases with diagnostic histopathological features of PLNTY (10 female; median age, 16 years; range, 5–52). Patients frequently presented with seizures (9 of 12 with available history) and temporal lobe tumors (9 of 13). MAPK pathway activating alterations were identified in all 13 cases. Fusions were present in the 7 youngest patients: FGFR2-CTNNA3 (n = 2), FGFR2-KIAA1598 (FGFR2-SHTN1) (n = 1), FGFR2-INA (n = 1), FGFR2-MPRIP (n = 1), QKI-NTRK2 (n = 1), and KIAA1549-BRAF (n = 1). BRAF V600E mutation was present in 6 patients (17 years or older). Two fusion-positive cases additionally harbored TP53/RB1 abnormalities suggesting biallelic inactivation. Copy number changes predominantly involving whole chromosomes were observed in all 10 evaluated cases, with losses of chromosome 10q occurring with FGFR2-KIAA1598 (SHTN1)/CTNNA3 fusions. The KIAA1549-BRAF and QKI-NTRK2 fusions were associated respectively with a 7q34 deletion and 9q21 duplication. This study shows that despite its name, PLNTY also occurs in older adults, who frequently show BRAF V600E mutation. It also expands the spectrum of the MAPK pathway activating alterations associated with PLNTY and demonstrates recurrent chromosomal copy number changes consistent with chromosomal instability.

scholarly journals Heterogeneity in Mitogen-Activated Protein Kinase (MAPK) Pathway Activation in Uveal Melanoma With Somatic GNAQ and GNA11 Mutations

2019 ◽  
Vol 60 (7) ◽  
pp. 2474 ◽  
Author(s):  
Getachew Boru ◽  
Colleen M. Cebulla ◽  
Klarke M. Sample ◽  
James B. Massengill ◽  
Frederick H. Davidorf ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Uveal Melanoma ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Pathway Activation ◽  
Mitogen Activated Protein

scholarly journals PTEN Loss-of-Function Alterations Are Associated With Intrinsic Resistance to BRAF Inhibitors in Metastatic Melanoma

2017 ◽  
pp. 1-15 ◽  
Author(s):  
Federica Catalanotti ◽  
Donavan T. Cheng ◽  
Alexander N. Shoushtari ◽  
Douglas B. Johnson ◽  
Katherine S. Panageas ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Tumor Regression ◽  
Braf Inhibitor ◽  
Molecular Signature ◽  
Braf Inhibitors ◽  
Next Generation ◽  
Loss Of Function ◽  
Intrinsic Resistance ◽  
Braf Mutant ◽  
Generation Sequencing

Purpose The clinical use of BRAF inhibitors in patients with melanoma is limited by intrinsic and acquired resistance. We asked whether next-generation sequencing of pretreatment tumors could identify coaltered genes that predict for intrinsic resistance to BRAF inhibitor therapy in patients with melanoma as a prelude to rational combination strategies. Patients and Methods We analyzed 66 tumors from patients with metastatic BRAF-mutant melanoma collected before treatment with BRAF inhibitors. Tumors were analyzed for > 250 cancer-associated genes using a capture-based next-generation sequencing platform. Antitumor responses were correlated with clinical features and genomic profiles with the goal of identifying a molecular signature predictive of intrinsic resistance to RAF pathway inhibition. Results Among the 66 patients analyzed, 11 received a combination of BRAF and MEK inhibitors for the treatment of melanoma. Among the 55 patients treated with BRAF inhibitor monotherapy, objective responses, as assessed by Response Evaluation Criteria in Solid Tumors (RECIST), were observed in 30 patients (55%), with five (9%) achieving a complete response. We identified a significant association between alterations in PTEN that would be predicted to result in loss of function and reduced progression-free survival, overall survival, and response grade, a metric that combines tumor regression and duration of treatment response. Patients with melanoma who achieved an excellent response grade were more likely to have an elevated BRAF-mutant allele fraction. Conclusion These results provide a rationale for cotargeting BRAF and the PI3K/AKT pathway in patients with BRAF-mutant melanoma when tumors have concurrent loss-of-function mutations in PTEN. Future studies should explore whether gain of the mutant BRAF allele and/or loss of the wild-type allele is a predictive marker of BRAFi sensitivity.

scholarly journals Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600–Mutant Colorectal Cancer

2015 ◽  
Vol 33 (34) ◽  
pp. 4023-4031 ◽  
Author(s):  
Ryan B. Corcoran ◽  
Chloe E. Atreya ◽  
Gerald S. Falchook ◽  
Eunice L. Kwak ◽  
David P. Ryan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Protein Kinase ◽  
Partial Response ◽  
Microsatellite Instability ◽  
Mutational Analysis ◽  
Braf Inhibitor ◽  
Complete Response ◽  
Mitogen Activated Protein Kinase ◽  
Pik3ca Mutations ◽  
Mitogen Activated Protein

Purpose To evaluate dabrafenib, a selective BRAF inhibitor, combined with trametinib, a selective MEK inhibitor, in patients with BRAF V600–mutant metastatic colorectal cancer (mCRC). Patients and Methods A total of 43 patients with BRAF V600–mutant mCRC were treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily), 17 of whom were enrolled onto a pharmacodynamic cohort undergoing mandatory biopsies before and during treatment. Archival tissues were analyzed for microsatellite instability, PTEN status, and 487-gene sequencing. Patient-derived xenografts were established from core biopsy samples. Results Of 43 patients, five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response > 36 months; 24 patients (56%) achieved stable disease as best confirmed response. Ten patients (23%) remained in the study > 6 months. All nine evaluable during-treatment biopsies had reduced levels of phosphorylated ERK relative to pretreatment biopsies (average decrease ± standard deviation, 47% ± 24%). Mutational analysis revealed that the patient achieving a complete response and two of three evaluable patients achieving a partial response had PIK3CA mutations. Neither PTEN loss nor microsatellite instability correlated with efficacy. Responses to dabrafenib plus trametinib were comparable in patient-derived xenograft–bearing mice and the biopsied lesions from each corresponding patient. Conclusion The combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600–mutant mCRC. Mitogen-activated protein kinase signaling was inhibited in all patients evaluated, but to a lesser degree than observed in BRAF-mutant melanoma with dabrafenib alone. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen. Additional studies targeting the mitogen-activated protein kinase pathway in this disease are warranted.

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