Blodprov för att upptäcka läkemedelsresistens hos patient

Forskare från Australien har via ett enkelt blodprov kunnat påvisa varför en viss grupp av cancerpatienter inte svarar på insatt cancerbehandling,via läkemedel (PARP hämmare). Studien har utgått från kvinnor med diagnostiserad äggstocks och bröstcancer där traditionella cancerläkemedel inte gett förväntad effekt på samtliga patienter.För vissa uteblir effekten helt vilket förbryllat läkarkåren,men ser man det resultatet på ett tidigt stadium finns alternativa läkemedel att sätta in som förhoppningsvis räddar större delen av patienterna.Tyvärr är återfallen hos dessa patienter stor. PARP står för Poly-Adp-Ribose-Polymerase och är ett protein (enzym) som finns i våra celler med uppgift att reparera skadade celler. Som jag förstår det kan detta protein inte urskilja cancerceller från friska celler utan stärker istället cancercellernas utveckling. Forskare har konstaterat detta och nyligen hittat sätt att hämma (Inhibit) detta protein hos cancerdrabbade,inledningsvis bröst prostata och äggstockscancrar.

Tillsammans med läkarkåren har man stora förhoppningar att PARP Inhibitors även kommer ha effekt på följande områden : 

• lung cancer
• pancreatic cancer
• head and neck cancer
• a type of brain tumour called glioblastoma 
• cancer of the stomach and food pipe (oesophagus)
• womb and cervical cancer
• kidney cancer
• children and young people whose cancer has come back 

Forskning på dessa områden med PARP Inhibitors försiggår med stor optimism. Ex denna.
Dock har användande av PARP hämmare visat sig vara ineffektiva hos en del av mottagarna vilket som sagt förbryllat forskare som läkarkår. I den Australiensiska studien visar forskarna nu anledningen. Länk

Posted: 20 November 2024

WEHI researchers have found a new way to predict a subset of patients who are likely to become resistant to PARP inhibitors (PARPi), a key therapy used to treat ovarian and breast cancers in Australia.
Using patient blood samples, the research team has been able to detect, for the first time, a specific process that can make ovarian cancer cells resistant to PARPi treatment – a significant finding that could enable the early detection of patients who won’t respond well to the therapy.
Medical researchers can immediately start to look for this form of resistance using tests that are currently being used in research settings and soon clinicians will be able to order these tests.

The breakthrough will improve patient care and potentially lead to clinical trials focused on overcoming drug resistance. It is anticipated that testing for this type of resistance, using a straightforward blood test, will eventually become a standard practice in both clinical and research environments.

More than 1700 women are diagnosed with ovarian cancer and over 20,000 people are diagnosed with breast cancer in Australia every year.
PARPi therapy has been a breakthrough for treating ovarian and breast cancers. In high-income countries, most patients with a DNA repair deficiency known as HRD – which can be caused by BRCA1 or BRCA2 mutations – are now receiving this treatment.

However, drug resistance remains a major challenge in PARPi therapy, with the majority of patients eventually experiencing relapse.

The process of splicing can cause cancer cells with mutations in genes, such as BRCA1, to become resistant to PARPi treatment. This means cancer cells with mutated BRCA1 genes can ‘skip over’ the mutation that the drug exploits, removing the drug vulnerability and causing the cancer to become resistant.
A new WEHI-led study has been able to detect DNA changes that cause this ‘splicing trick’ in the blood for the first time.

Co-first author and WEHI ovarian cancer researcher Dr Ksenija Nesic (Senior Research Officer
ACRF Cancer Biology and Stem Cells) said the findings solve a long-standing ‘blind spot’ in cancer research and could mark a turning point for cancer treatment.
“It’s been known for a while that splicing creates drug resistance. What we didn’t know was how the cancer cells do this and whether we could detect, measure and predict it in patients,” Dr Nesic said.

The findings show, for the first time, that this form of drug resistance can be detected in a subset of ovarian cancer patients through a blood test, or by examining the patient’s tumour itself. Specifically, the study identified this drug resistance in ovarian cancer patients who have mutations in the BRCA1 gene.

“This could be transformative for the cohort of ovarian cancer patients who have mutations in the BRCA1 gene, and potentially for other ovarian cancer patients too,” Dr Nesic said. “We are hopeful that further research will reveal similar splicing mechanisms in BRCA2 and other genes that relate to HRD.”
HRD (homologous recombination deficiency) is found in approximately 50% of ovarian cancer patients. Among these patients, about half have mutations in the BRCA1 or BRCA2 genes.
“The findings could revolutionise patient care, as doctors will now know they can look for splicing changes and more importantly, how to look,” Dr Nesic said.

Existing tests that show these changes are currently being used in research settings. These include DNA sequencing of a patient’s tumour or detecting cancer DNA in the blood. Soon clinicians will be able to order these tests directly and look out for this form of resistance.

It is hoped that testing for this type of resistance, in the form of a simple blood test, will eventually become standard practise in clinical as well as research settings.

“The discovery is profound because it opens up an avenue to monitor for drug resistance, where clinicians can in the future easily detect altered splicing of genes for BRCA1 and potentially for other genes involved in HRD, as their patient stops responding to therapy,” Dr Nesic said.
“While there are many types of resistance to PARP inhibitors, being able to identify those patients who are no longer going to respond to PARPi treatment early, enables better decision-making – meaning patients can be moved onto the next best therapy.

“The ultimate goal is to stop drug resistance in its tracks, for PARPi and for other types of drug resistance too. This research brings us closer to achieving this.”

Big leap for personalised treatment

The identification of the splicing mechanism offers a non-invasive method for monitoring PARPi resistance, potentially predicting this type of resistance. Importantly, it allows for early detection and better tailoring of cancer therapies for individual patients.

Senior co-author and cancer genetics specialist Associate Professor Matthew Wakefield said the findings could be revolutionary for ovarian cancer patients with an HRD gene mutation, currently being treated with PARPi therapy.
“Cancers becoming resistant to therapy is a big issue with targeted drugs like PARP inhibitors,” Assoc Prof Wakefield said.

“Being able to spot drug resistance early with a blood test, and switch to another treatment to avoid the resistance, will allow people to continue to control their cancer more successfully.
“It is a significant finding that will help patients stay healthier for longer.”

Min kommentar
Denna studie kan visa sig ha svaret på 2 saker :
1. Varför fungerar inte detta högst lovande (och framtida breda) läkemedel på samtliga cancerdrabbade?
2. Hur får man reda på enskild resistens tidigt i behandlingen,eller helst innan behandlingen?

Studien är av största betydelse för alla nuvarande som kommande cancerpatienter där PARP hämmande läkemedel används eller kommer användas.Den öppnar även upp för annan idag oförklarlig resistens mot givna läkemedel. Svar på detta hittas alltså i patientens eget blodprov.

Har detta då någon relevans för PHI och HoloMonitor?
Svaret på denna 10 000 kronorsfråga har jag inte tillräcklig kunskap för att kunna svara 100% ja eller nej på.

Dock vet vi att HoloMonitor är synnerligen användbart att via blodprov studera celler. Tänk ex Glyco.
Vi vet även att PHI har planer för att komma i kliniskt användande med HoloMonitor.

Och vi vet även att PHI har planer för att HoloMonitor ska användas vid personligt anpassad cancervård (vid sängkanten beskrivet). Tänk här info jag lämnat om vad som händer i England. Ex här och här.

Med den begränsade kunskap jag har ställer jag mig frågan om denna studie öppnar upp för PHI och HoloMonitor att användas i ett helt nytt område,läkemedelsresistens?
Vad tror ni? Mvh the99