2 augustus 2023: Bronnen verschillende internationale media en persbericht City of Hope

Professor Linda Malkas, ontdekker en ontwikkelaar van een 'kankerpil' die in laboratoriumstudies en dierstudies alle solide tumoren zou hebben vernietigd heeft afgelopen week bekend gemaakt dat de eerste kankerpatiënt die deze 'kankerpil' kreeg toegediend in een fase I studie in combinatie met een vorm van chemotherapie het uitstekend doet. De kankerpil wordt AOH1996 genoemd en is een zogeheten prolifererend celnucleair antigeen (PCNA)-remmer.

Onderzoekers van City of Hope, een van de grootste kankeronderzoeks- en behandelingsorganisaties in de Verenigde Staten, hebben vandaag een nieuwe studie gepubliceerd waarin wordt uitgelegd hoe ze een eiwit namen, het prolifererend celnucleair antigeen (PCNA), waarvan men dacht dat het te uitdagend was voor gerichte therapie, en Professor Linda Malkas samen met collega's ontwikkelden een gerichte chemotherapie die in preklinisch onderzoek alle solide tumoren lijkt te vernietigen.
De experimentele pil AOH1996 is genoemd naar een meisje wat overleed aan haar vorm van kanker, en is effectief gebleken in preklinisch onderzoek naar de behandeling van cellen afkomstig van borstkanker, prostaatkanker, hersenkanker, eierstokkanker, baarmoederhalskanker, huidkanker en longkanker.

The City of Hope-developed small molecule AOH1996 targets a cancerous variant of the protein PCNA. In its mutated form, PCNA is critical in DNA replication and repair of all expanding tumors. Here we see untreated cancer cells (left) and cancer cells treated with AOH1996 (right) undergoing programmed cell death (violet). (Photo credit: City of Hope)

“Door ons op PCNA te richten, remmen we de complexe machinerie om cellulaire groei en proliferatie te stoppen. Dit is een nieuwe manier om kankercellen te doden of op zijn minst te vertragen,"aldus Vincent Chung, M.D. die onderzoeksprofessor is bij de afdeling Medical Oncology & Therapeutics Research van City of Hope en hoofdonderzoeker in de klinische proef.

Professor Linda Malkas zegt dat andere gerichte therapieën, zoals immuuntherapie met checkpoint-remmers, die de groei en verspreiding van kanker remmen, ontelbare kankerpatiënten hebben geholpen, eraan toevoegend dat AOH1996 misschien op een dag een door de Amerikaanse Food and Drug Administration goedgekeurde tumorremmer zal zijn die in combinatie met bestaande therapieën zou kunnen worden gebruikt. om zowel kankerdodende effecten te versterken als bijwerkingen gerelateerd aan levensreddende kankerbehandelingen te verminderen.

Bovenstaande zijn enkele citaten vertaald uit een langer persbericht van City of Hope.

Oct. 19, 2022

CONTACT
Zen Logsdon
626-409-9367
zlogsdon@coh.org

The Phase 1 clinical trial tests the safety of providing City of Hope-developed AOH1996 to people with reoccurring solid tumors.

LOS ANGELES — City of Hope, one of the largest cancer research and treatment organizations in the United States, today announced that the first patient to receive its novel, promising cancer medicine AOH1996 is doing well. The Phase 1 clinical trial testing the safety of a potentially cancer-stopping therapeutic developed by City of Hope in people with reoccurring solid tumors is expected to continue for the next two years. The investigational pill has been effective in preclinical research treating cells derived from breast, prostate, brain, ovarian, cervical, skin and lung cancers.

Linda Malkas, Ph.D., professor in City of Hope’s Department of Molecular Diagnostics & Experimental Therapeutics, has been working on the research and subsequent discovery and development of AOH1996 for 20 years. AOH1996 is named after Anna Olivia Healey, a young girl born in 1996 who unfortunately was not able to beat cancer. AOH1996 is exclusively licensed by City of Hope to RLL, LLC, a biotechnology company that Malkas co-founded.

Malkas believed that proliferating cell nuclear antigen (PCNA), which plays an essential role in the replication and repair of cells, would be a less toxic cancer therapy that targets mutated cancer cells while leaving normal cells alone. The treatment has been shown in preclinical research to target PCNA and inhibit the growth and spread of a broad range of human cancer cells. The research protocol notes that AOH1996 is not toxic to healthy cells and that treatment with this medicine both pauses cell DNA synthesis and inhibits DNA repair, leading to a type of cell death known as apoptosis in the cancer cells.

“Imagine cancer as the water filling up a bathtub. Left unchecked, the tumors or water will eventually overflow and damage other parts of your home. The treatment my team at City of Hope created is akin to a watchful homeowner who shuts the water off — stopping the spread of tumors to other parts of the metaphorical house — and then drains the tub, eliminating the cancer,” said Malkas, co-investigator in the trial and the M.T. & B.A. Ahmadinia Professor in Molecular Oncology.

Vincent Chung, M.D., added, “By targeting PCNA, we are inhibiting the complex machinery to stop cellular growth and proliferation. This is a new way of trying to kill cancer cells or at least to slow it down.” He is a research professor in City of Hope’s Department of Medical Oncology & Therapeutics Research and principal investigator in the clinical trial.

The Phase 1 clinical trial is open at City of Hope Los Angeles. Its objective is to determine the maximum tolerated dose of the investigational pill, AOH1996, and to evaluate the medicine for preliminary efficacy. Eligible patients include adults with solid tumors who have not found standard treatments effective. Participating patients will be asked to take the medication in pill form twice a day.

“Since many patients’ cancers become resistant to our standard therapies, we need new therapeutics with new mechanisms of action — for example, non-cross resistant. AOH1996 is just that kind of new therapy,” said Daniel Von Hoff, M.D., of the Molecular Medicine Division at the Translational Genomics Research Institute, part of City of Hope, and an advisor on the study. “Congratulations to Dr. Malkas and the City of Hope team on this new invention.”

Malkas said other targeted therapies, like checkpoint inhibitors, that inhibit the growth and spread of cancer have helped innumerable cancer patients, adding that perhaps one day AOH1996 will be a U.S. Food and Drug Administration-approved inhibitor that could be used in combination with existing therapies to both enhance cancer-killing effects as well as decrease side effects related to lifesaving cancer treatments.

With the infrastructure and support of City of Hope, Malkas was able to commercialize her basic research, moving her promising laboratory discovery into a clinical trial for people who need the therapies of tomorrow today. City of Hope provided structure, experts and even GMP (good manufacturing practice) facilities to manufacture her medicine.

City of Hope is devoted to supporting research and development and has infrastructure that is tailor-made to accelerate innovations from the lab to patients. This system includes everything ranging from funding support to access to counsel from internal and external drug development specialists. City of Hope's R&D apparatus leverages the combination of its fundamental strength in basic science and its patient-care focus as a comprehensive cancer center.

Individuals interested in this clinical trial should review the eligibility requirements at clinicaltrials.gov. If they believe they are eligible, they can call 626-218-1133 or visit City of Hope’s clinical trials webpage.

Voor artsen en wetenschappers hier een studie hoe AOH1996 precies werkt. Studie is gepubliceerd 1 augustus 2023

Small molecule targeting of transcription-replication conflict for selective chemotherapy

Open AccessPublished:August 01, 2023DOI:https://doi.org/10.1016/j.chembiol.2023.07.001

Highlights

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Crystallography-directed medicinal chemistry identifies a PCNA ligand (AOH1996)
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AOH1996 enhances PCNA and RPB1 interaction and interferes with TRC resolution
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AOH1996 induces DNA double-stranded breaks in a transcription dependent manner
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Given orally, AOH1996 suppresses tumor growth but causes no discernable side effect

Summary

Targeting transcription replication conflicts, a major source of endogenous DNA double-stranded breaks and genomic instability could have important anticancer therapeutic implications. Proliferating cell nuclear antigen (PCNA) is critical to DNA replication and repair processes. Through a rational drug design approach, we identified a small molecule PCNA inhibitor, AOH1996, which selectively kills cancer cells. AOH1996 enhances the interaction between PCNA and the largest subunit of RNA polymerase II, RPB1, and dissociates PCNA from actively transcribed chromatin regions, while inducing DNA double-stranded breaks in a transcription-dependent manner. Attenuation of RPB1 interaction with PCNA, by a point mutation in RPB1’s PCNA-binding region, confers resistance to AOH1996. Orally administrable and metabolically stable, AOH1996 suppresses tumor growth as a monotherapy or as a combination treatment but causes no discernable side effects. Inhibitors of transcription replication conflict resolution may provide a new and unique therapeutic avenue for exploiting this cancer-selective vulnerability.