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Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
Published on: December 26, 2016
Combinatorial screen with apoptosis pathway targeted agents alrizomadlin, pelcitoclax, and dasminapant in multi-cell
Nathan P Coussens1, Thomas S Dexheimer1, Thomas Silvers1
1Molecular Pharmacology Laboratory, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
Abstract:
Apoptosis, or programmed cell death, plays a critical role in maintaining tissue homeostasis by eliminating damaged or abnormal cells. Dysregulation of apoptosis pathways is a hallmark of cancer, allowing malignant cells to evade cell death and proliferate uncontrollably. Targeting apoptosis pathways has emerged as a promising therapeutic strategy in cancer treatment, aiming to restore the balance between cell survival and death. The MDM2 inhibitor alrizomadlin, the Bcl-2/Bcl-xL inhibitor pelcitoclax, and the IAP family inhibitor dasminapant were evaluated both individually and in combinations with standard of care and investigational anticancer small molecules in a spheroid model of solid tumors. The multi-cell type tumor spheroids were grown from human endothelial cells and mesenchymal stem cells combined with human malignant cells that were either established or patient-derived cell lines from the NCI Patient-Derived Models Repository. The malignant cell lines were derived from a range of solid tumors including uterine carcinosarcoma, synovial sarcoma, rhabdomyosarcoma, soft tissue sarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor (MPNST), pancreas, ovary, colon, breast, and small cell lung cancer. Interactions were observed from combinations of the apoptosis pathway targeted agents. Additionally, interactions were observed from combinations of the apoptosis pathway targeted agents with other agents, including PARP inhibitors, the XPO1 inhibitor eltanexor, and the PI3K inhibitor copanlisib. Enhanced activity was also observed from combinations of the apoptosis pathway targeted agents with MAPK pathway targeted agents, including the MEK inhibitor cobimetinib as well as adagrasib and MRTX1133, which specifically target the KRAS G12C and G12D variants, respectively.
Insights
Targeting apoptosis pathways with novel agents like alrizomadlin, pelcitoclax, and dasminapant shows promise in solid tumors. Combinations with other targeted therapies, including MAPK inhibitors, enhance anti-cancer activity in diverse cancer models.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Apoptosis (programmed cell death) is crucial for tissue homeostasis.
- Dysregulated apoptosis is a key feature of cancer, enabling tumor cell survival and proliferation.
- Targeting apoptosis pathways offers a promising strategy for cancer treatment.
Purpose of the Study:
- To evaluate the efficacy of MDM2 inhibitor alrizomadlin, Bcl-2/Bcl-xL inhibitor pelcitoclax, and IAP inhibitor dasminapant in solid tumor models.
- To investigate the synergistic effects of these agents in combination with standard and investigational anticancer drugs.
- To explore novel combination strategies for enhancing anti-cancer activity.
Main Methods:
- Utilized multi-cell type tumor spheroids derived from various solid tumor cell lines (e.g., uterine carcinosarcoma, sarcoma, pancreas, breast).
- Assessed individual and combined effects of apoptosis-targeting agents (alrizomadlin, pelcitoclax, dasminapant).
- Evaluated combinations with PARP inhibitors, XPO1 inhibitor eltanexor, PI3K inhibitor copanlisib, and MAPK pathway inhibitors (cobimetinib, adagrasib, MRTX1133).
Main Results:
- Observed interactions and enhanced activity from combinations of apoptosis-targeting agents.
- Demonstrated improved efficacy when combining apoptosis inhibitors with other targeted therapies, including PARP, XPO1, PI3K, and MAPK pathway inhibitors.
- Specific combinations with MAPK pathway agents targeting KRAS variants showed enhanced anti-cancer effects.
Conclusions:
- Apoptosis-targeting agents show potential as monotherapies and in combination regimens for solid tumors.
- Combination strategies involving apoptosis inhibitors and other targeted agents, particularly MAPK pathway inhibitors, can overcome resistance and enhance therapeutic outcomes.
- These findings support the development of novel combination therapies for diverse solid malignancies.
