Scientists at The Institute of Cancer Research, London, have figured out a way to predict how long prostate cancer patients will benefit from the drug olaparib using a simple blood test. It turns out cancer cells are quite sneaky and can develop resistance to olaparib, even bringing back genes they were missing before!
The good news is that knowing this will help doctors personalize treatment and potentially develop new drugs to outsmart these crafty cancer cells. (I wanted to say bastard but my wife said crafty is more appropriate!)
Definitely some good information, they don't go deep enough into explaining what they're watching, etc. But not necessarily good news, lol. Wasn't aware that the PARP inhibitors suffered the same resistance mechanisms as other drugs. Interesting none the less, that is for posting!
I would try with every immune system stimulant (including white button mushrooms or their extract) plus physical activity (add some extra activity with an electro stimulator since it seems to work well for cancer control). There are drugs that are being tested for that scope but I think we cannot get them yet.
I take my share of supplements, but with a hope for delaying castration resistance I take mainly sulforaphane and fish oil, based on the not so rich literature available!
Thanks Max. my father takes cocktail of Turkey Tail + Reishi + Chaga + AHCC + Maitake + IP6 + Fucoidan + lactoferrin twice a day. He takes sulforaphane and SPM fish oil seprately. His PSA increased from 0.17 to 0.27 in 4 months which happened last year too so i am not yet sure if he is getting resistent or its just a PSA bounce.
You're absolutely right—cancer cells are incredibly adept at adapting to treatments, including targeted therapies like olaparib, a PARP inhibitor. This phenomenon of resistance can involve several strategies, one of which is known as restoration of homologous recombination (HR) repair.
Olaparib works by exploiting defects in HR repair, a pathway critical for repairing double-strand DNA breaks. Tumors with mutations in BRCA1 or BRCA2, for example, are especially sensitive to PARP inhibitors because they lack effective HR repair mechanisms. However, over time, cancer cells can:
1. Restore HR Function: Some cancer cells regain function of the damaged HR pathway. This can happen if the cell repairs or bypasses the mutation in the BRCA genes, restoring their ability to repair DNA damage effectively. As a result, the cancer cells no longer rely on PARP for DNA repair and become resistant to the inhibitor.
2. Upregulate Drug Efflux: Cancer cells may increase the expression of proteins like P-glycoprotein that pump olaparib out of the cell, reducing its effectiveness.
3. Develop Additional Mutations: Secondary mutations can disable the mechanisms that made cells sensitive to PARP inhibitors in the first place.
4. Alter DNA Damage Responses: Cancer cells might adapt by relying on alternative DNA repair pathways, bypassing the need for HR repair entirely.
Understanding these resistance mechanisms is critical for designing combination therapies or second-line treatments that can overcome or prevent resistance. Research continues to explore ways to stay ahead of these adaptations, such as combining PARP inhibitors with drugs that target other repair pathways or immune checkpoint inhibitors to enhance tumor vulnerability.
Q. Could we conclude that delayed use of parpi is a preferred strategy in cancer treatment? Olaparib should be used last after darolutamide failed? Or are there some advantages of early use of olaparib parallel with darolutamide?
A. The timing and sequencing of PARP inhibitors like olaparib in cancer treatment depend on several factors, including the type of cancer, its stage, and the patient’s genetic profile. Whether to delay or use olaparib early in combination with other therapies, such as darolutamide (an androgen receptor inhibitor used for prostate cancer), requires balancing potential benefits and drawbacks. Here's a breakdown:
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Advantages of Delayed Use of Olaparib (After Darolutamide Failure)
1. Preserving Options:
Using darolutamide first allows targeting androgen receptor (AR)-dependent pathways. If resistance develops, olaparib can then exploit DNA repair deficiencies for patients with relevant mutations (e.g., BRCA or ATM mutations).
This staggered approach helps avoid prematurely inducing resistance mechanisms, such as reversion mutations.
2. Resistance Management:
Delayed use avoids the potential for olaparib to select for resistant clones earlier in the treatment course.
3. Side Effect Management:
Delaying olaparib reduces the risk of cumulative toxicity, particularly in patients who might benefit from prolonged androgen receptor-targeted therapy alone.
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Advantages of Early Use of Olaparib (Parallel with Darolutamide)
1. Synergistic Effects:
Combining olaparib with darolutamide may have a synergistic effect, as AR signaling can influence DNA repair pathways. Targeting both simultaneously might prevent cancer cells from exploiting cross-pathway interactions.
Trials have shown that combining PARP inhibitors with AR inhibitors can delay disease progression in some patients.
2. Maximizing Initial Response:
Patients with DNA damage repair (DDR) gene mutations may derive the greatest benefit when both AR and DDR pathways are simultaneously targeted.
Early combination therapy could reduce tumor heterogeneity, making it harder for resistant clones to emerge.
3. Targeting Aggressive Disease:
Advanced or aggressive cancers often adapt quickly to single-agent therapies. Combining agents early may be more effective in controlling tumor growth.
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Key Considerations for Timing Decisions
1. Patient-Specific Factors:
Genetic profiling is critical. Patients with BRCA2 or other DDR mutations may benefit from earlier olaparib use.
Tumor burden and aggressiveness can also influence whether combination therapy is warranted upfront.
2. Current Evidence:
Trials like PROfound and TALAPRO-2 have highlighted the benefit of olaparib in specific patient populations. Some studies suggest improved progression-free survival with early combination therapy.
However, risks such as increased toxicity and earlier resistance development must be weighed against potential benefits.
3. Evolving Paradigms:
Research into the optimal sequencing of therapies is ongoing. Some experts advocate for adaptive treatment strategies where therapy is adjusted based on real-time monitoring (e.g., blood-based biomarkers like those predicting reversion mutations).
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Conclusion
There isn’t a one-size-fits-all answer. In general:
Delayed use of olaparib may be preferred in patients without immediate signs of DDR pathway deficiencies or with stable disease, preserving it as a second-line option.
Early combination therapy may be advantageous in patients with aggressive disease or known DDR mutations, where maximizing initial response outweighs the risks.
Ultimately, the choice depends on a patient’s specific clinical and genetic context, and it’s best guided by a personalized treatment plan developed by oncologists familiar with the latest evidence.
Olaparib’s Effectiveness Duration in Prostate Cancer TreatmentScientists have developed a method using a simple blood test to predict the duration of a prostate cancer patient’s response to the PARP inhibitor drug olaparib. This discovery, published in Cancer Cell, comes from researchers at The Institute of Cancer Research, London.
A strong link was found between the number of “reversion mutations” in a patient’s DNA and their survival time. Reversion mutations restore function to mutated genes involved in DNA repair.
After four months of olaparib treatment, patients with a high number of these mutations had an average survival time of 13.9 months, while those with a lower number lived an average of 21.4 months.
Olaparib works by preventing cancer cells from repairing their DNA.
The research focused on patients with advanced prostate cancer who had mutations in genes responsible for DNA damage repair, and who initially responded well to olaparib. The study found that olaparib treatment can actually cause some tumors to regain the ability to repair DNA, even in tumors missing the BRCA2 gene.
This finding is significant because it explains how resistance to the drug develops, and it may lead to the development of new treatments to prevent this resistance.
Being able to predict when and how patients will develop resistance to olaparib is critical for personalizing treatment strategies. Doctors can use this information to decide when to switch patients to different treatments, and researchers can focus on developing new therapies to target the specific mechanisms of resistance.
A. This breakthrough is a crucial step toward understanding and managing resistance to olaparib in advanced prostate cancer. The ability to predict how long patients will respond to the drug using a simple blood test is not only a leap forward for personalized medicine but also sheds light on the adaptive capabilities of cancer cells.
Key Insights:
1. Reversion Mutations and Survival:
Reversion mutations restore the function of previously inactivated DNA repair genes, such as BRCA2.
Patients with higher levels of these mutations had shorter survival times (13.9 months on average) compared to those with fewer mutations (21.4 months).
This suggests reversion mutations play a direct role in enabling resistance to olaparib.
2. Mechanism of Resistance:
Initially, olaparib is highly effective in tumors deficient in DNA repair due to mutations in genes like BRCA2.
Over time, olaparib can select for cancer cells that acquire reversion mutations, restoring their ability to repair DNA and rendering the drug ineffective.
3. Clinical Implications:
The blood test helps identify patients who are likely to develop resistance early, enabling timely intervention.
It could inform decisions about switching therapies before resistance fully develops, improving outcomes.
This approach is particularly valuable for patients with advanced prostate cancer who have limited treatment options.
4. Future Directions:
Researchers can focus on therapies that either delay or prevent the emergence of reversion mutations.
Combining olaparib with drugs targeting other repair pathways (like ATR or WEE1 inhibitors) may improve its durability.
Studying the evolutionary dynamics of cancer cells under treatment pressure can guide the development of resistance-proof strategies.
This discovery emphasizes the importance of continuous monitoring during treatment and highlights the dynamic nature of cancer progression. It’s a significant step toward more tailored and effective management of advanced prostate cancer.
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