REAP · Repair of DNA lesions induced by platinum drugs
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2019-05-01 → 2021-04-30
- Финансиране от ЕС
- 186 167 €
- Участници
- 2
- Схема
- MSCA-IF-EF-ST
Линиите свързват координатора с партньорите.
Накратко на български
Молекулярните механизми за поправка на ДНК при рак на дебелото черво обясняват защо някои пациенти реагират по-добре на оксалиплатин, отколкото на цисплатин. Разбирането на тези процеси помага за откриването на маркери, които да определят най-подходящото лечение за всеки пациент.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Repair of DNA lesions induced by platinum drugs
The aim of the REAP 843630 was to understand the molecular principles underlying the tumor’s differential treatment response to platinum drugs and to identify novel predictive and prognostic markers. In gastrointestinal cancers, unlike in any other type of solid tumors, the responsiveness to oxaliplatin is superior to cisplatin. Hence, colon cancer is one of the few cancer types exclusively treated with oxaliplatin. Still, the sensitivity of colon tumors to this platinum drug varies between patients. The specificity of oxaliplatin for gastrointestinal cancers was not mechanistically explained to date and there were no clinical markers identified to pre-select oxaliplatin-susceptible patients to achieve the best treatment results. In order to address these points, we set to comprehensively explore the cellular processes that recognize and remove oxaliplatin and cisplatin-DNA lesions. Generation of DNA damage is the main mechanism of platinum drugs leading to tumor inhibition and DNA repair processes modulate the tumor response. We, therefore, hypothesized that cancer-specific differences in the repair of these lesions could explain distinct clinical efficiencies of platinum drugs. We observed that a subset of colon tumors is deficient in removing oxaliplatin-DNA lesions by one of the main DNA repair pathways, global-genome nucleotide excision repair (GG-NER). This pathway is represented by the rate-limiting activity of XPC protein. Based on this observation, we formulated three main objectives: Objective 1: Identify factors determining diverse XPC behavior on oxaliplatin versus cisplatin lesions. Objective 2: Identify the molecular mechanism of XPC regulation in oxaliplatin and cisplatin lesions recognition, and Objective 3: Identify DNA repair molecular signature in cancer patients’ tumors, related to treatment response to oxaliplatin.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
DNA damage-inducing platinum drugs, such as oxaliplatin and cisplatin, are used to treat about half of all patients receiving chemotherapy. Although potentially very efficient, many patients develop resistance for yet unrecognized reasons. Better understanding of the DNA damage response (DDR) to platinum-DNA lesions is therefore much needed for improving treatment outcomes. By performing DDR-dedicated CRISPR/Cas9 knockout screens, the applicant has shown that some cancer cells deficient in the major repair of bulky DNA lesions, global-genome nucleotide excision repair (GG-NER), are insensitive to oxaliplatin but sensitive to cisplatin. This striking difference remains as of yet unreported, but might explain differential responses of tumors to drugs. The aim of this proposal is to understand why GG-NER is unable to repair oxaliplatin lesions in particular genetic backgrounds. To do so, unbiased identification of genes differently mutated or expressed in oxaliplatin-sensitive versus insensitive cells will be followed by validation and in-depth functional characterization of identified targets. The ambition is to extrapolate experimental observations to translational knowledge. Validated targets will be studied in patient-derived tumor tissues as compared to nonmalignant tissues and related to patients’ treatment responses. Identification of genetic factors that regulate platinum lesions recognition by GG-NER will contribute to the understanding of molecular principles of platinum drugs cytotoxicity and might thus have considerable benefit on current cancer treatment schemes.The novelty of the pilot data, the unique multidisciplinary design of the project, the use of state-of-the-art molecular techniques and a collaboration with multiple European experts will ensure high scientific impact. Both, the applicant and the host will greatly benefit from the vital knowledge transfer. This project follows the European Union's commitment to cancer research.
Оригинален текст от CORDIS (на английски).
Участници
Връзки
Данни: CORDIS, © Европейски съюз