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Related Concept Videos

Targeted Cancer Therapies02:57

Targeted Cancer Therapies

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The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
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Combination Therapies and Personalized Medicine02:50

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Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
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The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

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Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
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The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
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Related Experiment Video

Updated: Dec 12, 2025

Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
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Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine

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Simultaneously Inhibiting BCL2 and MCL1 Is a Therapeutic Option for Patients with Advanced Melanoma.

Nabanita Mukherjee1, Carol M Amato2, Jenette Skees1

  • 1Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Mail Stop 8127, Aurora, CO 80045, USA.

Cancers
|August 9, 2020
PubMed
Summary

Targeting B-cell CLL/lymphoma 2 (BCL2) and myeloid cell leukemia sequence 1 (MCL1) with BH3 mimetics shows promise for advanced melanoma, especially in patients lacking BRAF mutations.

Keywords:
BH3 mimeticsBRAF-WTBRAF-mutantmelanomavenetoclax

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Tumor Engraftment in a Xenograft Mouse Model of Human Mantle Cell Lymphoma
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Tumor Engraftment in a Xenograft Mouse Model of Human Mantle Cell Lymphoma
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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genomics

Background:

  • Advanced melanoma, particularly rare subtypes like mucosal and acral melanoma, presents challenges for immune checkpoint blockade therapy, especially in patients lacking BRAF-V600E/K mutations.
  • Identifying novel therapeutic targets is crucial for refractory or ineligible patient populations.

Purpose of the Study:

  • To investigate the potential of BH3 mimetics targeting B-cell CLL/lymphoma 2 (BCL2) and myeloid cell leukemia sequence 1 (MCL1) as a therapeutic strategy for advanced melanoma.
  • To evaluate the efficacy of combining a BCL2 inhibitor (ABT-199) with an MCL1 inhibitor in various melanoma subtypes, with a focus on BRAF mutation status.

Main Methods:

  • Analysis of The Cancer Genome Atlas (TCGA) transcriptomic and proteomic data for differential expression of apoptosis molecules in melanomas with or without BRAF hotspot mutations.
  • In vitro and in vivo assessment of the combination therapy using two BH3 mimetics (ABT-199 and an MCL1 inhibitor) across cutaneous, mucosal, and acral melanoma cell lines.
  • Knockdown/knockout experiments to elucidate the role of pro-apoptotic BCL2 family members (BIM, NOXA, BID) in the observed cell death.

Main Results:

  • Higher BCL2 expression was observed in melanomas without BRAF hotspot mutations, suggesting BCL2 inhibition as a potential therapeutic avenue.
  • The combination of ABT-199 and an MCL1 inhibitor demonstrated potent cell death induction across diverse melanoma cell lines, including melanoma-initiating cells.
  • This combination therapy was found to be more effective in melanoma cells lacking BRAF-V600E/K mutations.
  • Knockdown/knockout studies indicated that BIM, NOXA, or BID are involved in the combination-induced apoptosis.

Conclusions:

  • The combination of MCL1 and BCL2 inhibitors represents a promising therapeutic strategy for advanced melanoma, particularly for patients with BRAF wild-type or rare melanoma subtypes.
  • This approach offers a potential treatment option for patients unresponsive or ineligible for current immune checkpoint blockade therapies.