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Published on: July 17, 2020
PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer
Sabina Luszczak1, Christopher Kumar1, Vignesh Krishna Sathyadevan1
1Molecular Diagnostics and Therapeutics Group, University College London, London, UK.
Abstract:
PIM kinases have been shown to play a role in prostate cancer development and progression, as well as in some of the hallmarks of cancer, especially proliferation and apoptosis. Their upregulation in prostate cancer has been correlated with decreased patient overall survival and therapy resistance. Initial efforts to inhibit PIM with monotherapies have been hampered by compensatory upregulation of other pathways and drug toxicity, and as such, it has been suggested that co-targeting PIM with other treatment approaches may permit lower doses and be a more viable option in the clinic. Here, we present the rationale and basis for co-targeting PIM with inhibitors of PI3K/mTOR/AKT, JAK/STAT, MYC, stemness, and RNA Polymerase I transcription, along with other therapies, including androgen deprivation, radiotherapy, chemotherapy, and immunotherapy. Such combined approaches could potentially be used as neoadjuvant therapies, limiting the development of resistance to treatments or sensitizing cells to other therapeutics. To determine which drugs should be combined with PIM inhibitors for each patient, it will be key to develop companion diagnostics that predict response to each co-targeted option, hopefully providing a personalized medicine pathway for subsets of prostate cancer patients in the future.
Insights
Targeting PIM kinases with combination therapies shows promise for prostate cancer. Co-targeting PIM may overcome resistance and reduce toxicity, paving the way for personalized treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- PIM kinases are implicated in prostate cancer progression, proliferation, and apoptosis.
- Upregulation of PIM kinases correlates with poor patient survival and treatment resistance.
- PIM kinase monotherapy faces challenges due to pathway compensation and toxicity.
Purpose of the Study:
- To explore the rationale for co-targeting PIM kinases in prostate cancer.
- To identify potential combination strategies for PIM inhibition.
- To investigate the potential of PIM-targeted therapies in personalized medicine.
Main Methods:
- Review of existing literature on PIM kinase function and therapeutic targeting.
- Identification of synergistic pathways and agents for combination therapy.
- Discussion of potential clinical applications, including neoadjuvant therapy.
Main Results:
- Co-targeting PIM with inhibitors of PI3K/mTOR/AKT, JAK/STAT, MYC, stemness, and RNA Polymerase I transcription is proposed.
- Combination with androgen deprivation, radiotherapy, chemotherapy, and immunotherapy is explored.
- Combined approaches may limit treatment resistance and sensitize cancer cells.
Conclusions:
- Combined PIM inhibition strategies offer a promising therapeutic avenue for prostate cancer.
- Development of companion diagnostics is crucial for personalized PIM-targeted therapy.
- Future research should focus on validating these combination approaches and developing predictive biomarkers.
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