Innovative Treatment Options of Plexiform Neurofibromas with MEK Inhibitors

Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15–20% before the advent of immunotherapy. Treatment with immune checkpoint inhibitors has increased long-term survival outcomes in patients with advanced melanoma to as high as 50% although individual response can vary greatly. A mutation within the MAPK pathway leads to uncontrollable growth and ultimately develops into cancer. The most common driver mutation that leads to this characteristic overactivation in the MAPK pathway is the B-RAF mutation. Current combinations of BRAF and MEK inhibitors that have demonstrated improved patient outcomes include dabrafenib with trametinib, vemurafenib with cobimetinib or encorafenib with binimetinib. Treatment with BRAF and MEK inhibitors has met challenges as patient responses began to drop due to the development of resistance to these inhibitors which paved the way for development of immunotherapies and other small molecule inhibitor approaches to address this. Resistance to these inhibitors continues to push the need to expand our understanding of novel mechanisms of resistance associated with treatment therapies. This review focuses on the current landscape of how resistance occurs with the chronic use of BRAF and MEK inhibitors in BRAF-mutant melanoma and progress made in the fields of immunotherapies and other small molecules when used alone or in combination with BRAF and MEK inhibitors to delay or circumvent the onset of resistance for patients with stage III/IV BRAF mutant melanoma.

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Recovery of energy from sludge – comparison of the various options

Water Science & Technology ◽

10.2166/wst.2004.0574 ◽

2004 ◽

Vol 50 (9) ◽

pp. 213-221 ◽

Cited By ~ 14

Author(s):

W.H. Rulkens ◽

J.D. Bien

Keyword(s):

Energy Source ◽

Low Temperature ◽

Organic Carbon ◽

Treatment Options ◽

Sludge Treatment ◽

Innovative Treatment ◽

Future Developments ◽

Treatment Processes ◽

Carbon Compounds

This paper gives a general discussion of existing sludge treatment processes and of innovative treatment options, especially focused on the valuable use of organic carbon compounds as an energy source. Attention is paid both to high and to low temperature processes and to combinations of these processes. Based on an assessment and comparison the most beneficial and sustainable options are identified and a rough indication is given of the possibilities for improvement and future developments.

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Non-Melanoma Skin Cancers: Biological and Clinical Features

International Journal of Molecular Sciences ◽

10.3390/ijms21155394 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5394

Author(s):

Mauro Cives ◽

Francesco Mannavola ◽

Lucia Lospalluti ◽

Maria Chiara Sergi ◽

Gerardo Cazzato ◽

...

Keyword(s):

Cell Carcinoma ◽

Clinical Features ◽

Clinical Presentation ◽

Treatment Options ◽

Biological Evolution ◽

Hedgehog Pathway ◽

Merkel Cell ◽

Innovative Treatment ◽

Skin Cancers ◽

Melanoma Skin

Non-melanoma skin cancers (NMSCs) include basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and Merkel cell carcinoma (MCC). These neoplasms are highly diverse in their clinical presentation, as well as in their biological evolution. While the deregulation of the Hedgehog pathway is commonly observed in BCC, SCC and MCC are characterized by a strikingly elevated mutational and neoantigen burden. As result of our improved understanding of the biology of non-melanoma skin cancers, innovative treatment options including inhibitors of the Hedgehog pathway and immunotherapeutic agents have been recently investigated against these malignancies, leading to their approval by regulatory authorities. Herein, we review the most relevant biological and clinical features of NMSC, focusing on innovative treatment approaches.

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Trametinib Induces Neurofibroma Shrinkage and Enables Surgery

Neuropediatrics ◽

10.1055/s-0039-1691830 ◽

2019 ◽

Vol 50 (05) ◽

pp. 300-303 ◽

Cited By ~ 9

Author(s):

Pia Vaassen ◽

Nikola Dürr ◽

Andreas Röhrig ◽

Rainer Willing ◽

Thorsten Rosenbaum

Keyword(s):

Vertebral Column ◽

Plexiform Neurofibroma ◽

Neurofibromatosis Type ◽

Mek Inhibitor ◽

Suppressor Gene ◽

Complete Disappearance ◽

Therapeutic Success ◽

Mek Inhibitors ◽

Plexiform Neurofibromas ◽

Peripheral Nerve Sheath Tumors

AbstractPlexiform neurofibromas are congenital peripheral nerve sheath tumors characteristic of neurofibromatosis type 1 (NF1)—a frequent neurocutaneous disorder caused by mutations of the NF1 tumor suppressor gene. Since plexiform neurofibromas are a major cause of the burden of disease and may also progress to malignancy, many efforts have been undertaken to find a cure for these tumors. However, neither surgery nor medication has so far produced a breakthrough therapeutic success. Recently, a clinical phase I study reported significant shrinkage of plexiform neurofibromas following treatment with the MEK inhibitor selumetinib. Here, we report an 11-year-old NF1 patient with a large plexiform neurofibroma of the neck that had led to a sharp-angled kinking of the cervical spine and subsequent myelopathy. Although surgical stabilization of the cervical vertebral column was urgently recommended, the vertebral column was inaccessible due to extensive tumor growth. In this situation, treatment with the MEK inhibitor trametinib was initiated which resulted in a 22% reduction in tumor volume after 6 months of therapy and finally enabled surgery. These data show that MEK inhibitors may not lead to complete disappearance of NF1-associated plexiform neurofibromas but can be an essential step in a multimodal therapeutic approach for these tumors. The course of our patient suggests that MEK inhibitors are likely to play a significant role in providing a cure for one of the most devastating manifestations of NF1.

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A patient with melanoma that became sensitized to immunotherapy after treatment with a CDK4/6 inhibitor

Immunotherapy ◽

10.2217/imt-2020-0139 ◽

2020 ◽

Vol 12 (12) ◽

pp. 861-867

Author(s):

Jacob Zaemes ◽

Ali Alzeer ◽

Kathryn Villa ◽

Michael Atkins

Keyword(s):

Metastatic Melanoma ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Poor Response ◽

Sustained Response ◽

Mek Inhibitors ◽

Preclinical Data ◽

Melanoma Treatment

Background: Despite the profound effect that checkpoint inhibitors and BRAF/MEK inhibitors have had on survival in patients with metastatic melanoma, treatment options remain limited for those who demonstrate poor response or develop resistance to these modalities. The prospect of tumor sensitization to these treatments is therefore an attractive one. Results: We describe the case of a patient who developed a sustained response to trametinib and pembrolizumab, despite prior resistance to both these therapies, after receiving treatment with a CDK4/6 inhibitor. Discussion: We further outline the preclinical data supporting a possible role for the use of CDK4/6 inhibitors in tumor sensitization to immunotherapy.

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Drug responses are conserved across patient-derived xenograft models of melanoma leading to identification of novel drug combination therapies

British Journal of Cancer ◽

10.1038/s41416-019-0696-y ◽

2019 ◽

Vol 122 (5) ◽

pp. 648-657 ◽

Cited By ~ 1

Author(s):

Ryan J. Ice ◽

Michelle Chen ◽

Max Sidorov ◽

Tam Le Ho ◽

Rinette W. L. Woo ◽

...

Keyword(s):

Metastatic Melanoma ◽

Antitumor Agents ◽

Treatment Options ◽

Braf Inhibitor ◽

Drug Combinations ◽

Response To Therapy ◽

Combination Therapies ◽

Mek Inhibitors ◽

Patient Derived Xenograft ◽

Novel Drug

Abstract Background Patient-derived xenograft (PDX) mouse tumour models can predict response to therapy in patients. Predictions made from PDX cultures (PDXC) would allow for more rapid and comprehensive evaluation of potential treatment options for patients, including drug combinations. Methods We developed a PDX library of BRAF-mutant metastatic melanoma, and a high-throughput drug-screening (HTDS) platform utilising clinically relevant drug exposures. We then evaluated 34 antitumor agents across eight melanoma PDXCs, compared drug response to BRAF and MEK inhibitors alone or in combination with PDXC and the corresponding PDX, and investigated novel drug combinations targeting BRAF inhibitor-resistant melanoma. Results The concordance of cancer-driving mutations across patient, matched PDX and subsequent PDX generations increases as variant allele frequency (VAF) increases. There was a high correlation in the magnitude of response to BRAF and MEK inhibitors between PDXCs and corresponding PDXs. PDXCs and corresponding PDXs from metastatic melanoma patients that progressed on standard-of-care therapy demonstrated similar resistance patterns to BRAF and MEK inhibitor therapy. Importantly, HTDS identified novel drug combinations to target BRAF-resistant melanoma. Conclusions The biological consistency observed between PDXCs and PDXs suggests that PDXCs may allow for a rapid and comprehensive identification of treatments for aggressive cancers, including combination therapies.

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IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma

Cancers ◽

10.3390/cancers13225863 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5863

Author(s):

Hima Patel ◽

Rosalin Mishra ◽

Nour Yacoub ◽

Samar Alanazi ◽

Mary Kate Kilroy ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Lines ◽

Treatment Options ◽

Acquired Resistance ◽

Resistant Cell ◽

Sequencing Analysis ◽

Mek Inhibitors ◽

Braf Mutant

The use of BRAF and MEK inhibitors for patients with BRAF-mutant melanoma is limited as patients relapse on treatment as quickly as 6 months due to acquired resistance. We generated trametinib and dabrafenib resistant melanoma (TDR) cell lines to the MEK and BRAF inhibitors, respectively. TDR cells exhibited increased viability and maintenance of downstream p-ERK and p-Akt as compared to parental cells. Receptor tyrosine kinase arrays revealed an increase in p-IGF1R and p-IR in the drug resistant cells versus drug sensitive cells. RNA-sequencing analysis identified IGF1R and INSR upregulated in resistant cell lines compared to parental cells. Analysis of TCGA PanCancer Atlas (skin cutaneous melanoma) showed that patients with a BRAF mutation and high levels of IGF1R and INSR had a worse overall survival. BMS-754807, an IGF1R/IR inhibitor, suppressed cell proliferation along with inhibition of intracellular p-Akt in TDR cells. Dual inhibition of IGF1R and INSR using siRNA reduced cell proliferation. The combination of dabrafenib, trametinib, and BMS-754807 treatment reduced in vivo xenograft tumor growth. Examining the role of IGF1R and IR in mediating resistance to BRAF and MEK inhibitors will expand possible treatment options to aid in long-term success for BRAF-mutant melanoma patients.

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