New hypotheses and opportunities in endocrine therapy: amplification of oestrogen-induced apoptosis
V Craig Jordan1, Joan S Lewis-Wambi, Roshani R Patel
1Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. v.craig.jordan@fccc.edu
Aims:
To outline the progress being made in the understanding of acquired resistance to long term therapy with the selective oestrogen receptor modulators (SERMs, tamoxifen and raloxifene) and aromatase inhibitors. The question to be addressed is how we can amplify the new biology of oestrogen-induced apoptosis to create more complete responses in exhaustively antihormone treated metastatic breast cancer.
Methods And Results:
Three questions are posed and addressed. (1) Do we know how oestrogen works? (2) Can we improve adjuvant antihormonal therapy? (3) Can we enhance oestrogen-induced apoptosis? The new player in oestrogen action is GPR30 and there are new drugs specific for this target to trigger apoptosis. Similarly, anti-angiogenic drugs can be integrated into adjuvant antihormone therapy or to enhance oestrogen-induced apoptosis in Phase II antihormone resistant breast cancer. The goal is to reduce the development of acquired antihormone resistance or undermine the resistance of breast cancer cells to undergo apoptosis with oestrogen respectively. Finally, drugs to reduce the synthesis of glutathione, a subcellular molecule compound associated with drug resistance, can enhance oestradiol-induced apoptosis.
Conclusions:
We propose an integrated approach for the rapid testing of agents to blunt survival pathways and amplify oestrogen-induced apoptosis and tumour regression in Phase II resistant metastatic breast cancer. This Pharma platform will provide rapid clinical results to predict efficacy in large scale clinical trials.
Insights
New strategies target acquired resistance to endocrine therapy in metastatic breast cancer. Researchers are exploring GPR30 agonists, anti-angiogenic drugs, and glutathione inhibitors to enhance oestrogen-induced apoptosis and improve treatment outcomes.
Area of Science:
- Oncology
- Endocrinology
- Pharmacology
Background:
- Acquired resistance to selective oestrogen receptor modulators (SERMs) and aromatase inhibitors limits long-term endocrine therapy efficacy in metastatic breast cancer.
- Understanding oestrogen signalling and apoptosis pathways is crucial for overcoming treatment resistance.
Purpose of the Study:
- To review progress in understanding acquired resistance to endocrine therapies for breast cancer.
- To explore strategies for amplifying oestrogen-induced apoptosis in hormone-resistant metastatic breast cancer.
Main Methods:
- Investigated the role of G-protein coupled receptor 30 (GPR30) in oestrogen action and its potential as a therapeutic target.
- Examined the integration of anti-angiogenic drugs into adjuvant antihormone therapy.
- Assessed the impact of glutathione synthesis inhibitors on oestradiol-induced apoptosis.
Main Results:
- GPR30 is identified as a key player in oestrogen action, with specific drugs targeting it to induce apoptosis.
- Anti-angiogenic agents show potential for combination therapy to enhance apoptosis in resistant breast cancer.
- Drugs reducing glutathione synthesis can augment oestradiol-induced apoptosis, potentially overcoming drug resistance.
Conclusions:
- An integrated approach is proposed for rapid testing of agents that blunt survival pathways and enhance apoptosis in resistant metastatic breast cancer.
- A pharmaceutical platform aims to accelerate clinical results for predicting efficacy in large-scale trials.
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