TORAK - Un nuovo bersaglio terapeutico per i tumori resistenti alle cure tradizionali: AKR1C3 (TORAK)
Tipologia
Progetti nazionali
Programma di ricerca
Fondazione CRT
Budget
€ 63.045,00
Periodo
12/09/2022 - 11/12/2024
Responsabile
Simonetta Oliaro Bosso
Partecipanti al progetto
- Oliaro Bosso Simonetta (Responsabile)
Descrizione del progetto
Il cancro è una patologia in costante crescita con 377.000 nuove diagnosi stimate nel 2021 solo in Italia (AIOM-AIRTUM). Secondo Il Registro dei Tumori Piemonte 88 piemontesi ricevono ogni giorno una diagnosi di tumore maligno, con una prevalenza di tumori prostatici negli uomini e mammari nelle donne (in aumento anche i tumori mammari triplo-negativi). Ai tumori in assoluto più frequenti, come i tumori alla mammella e alla prostata, si associano poi i tumori rari di difficile diagnosi e cura per gli insufficienti studi clinici presenti. Oggi le nuove tecniche diagnostiche e terapie disponibili hanno aumentato la sopravvivenza, ma per molti tumori aggressivi si ha ancora una prognosi infausta per la scarsità di efficaci terapie e, spesso, per l’insorgenza di resistenza a quelle presenti. C’è sempre maggiormente la necessità, quindi, di sviluppare terapie più potenti e, e soprattutto comprendere i meccanismi attraverso cui, spesso, le cellule tumorali riescono a sopravvivere e diventare resistenti alle terapie. Solo così si possono rendere le cure efficaci ed evitare lo svilupparsi di recidive a distanza, molto spesso più maligne e con esiti fatali.
La collaborazione tra enti di ricerca territoriali è vitale perché il Piemonte sia sempre in prima linea nella ricerca e nella cura dei tumori. UniTO (DSTF, DSCB e DDC) si unisce alla Fondazione FEET di Biella per consolidare una rete già esistente di eccellenze territoriali di ricerca in campo oncologico e proporre il progetto TORAK.
Il progetto mira, quindi, a potenziare la ricerca in ambito oncologico, sviluppando terapie più efficaci e durature contro i tumori più aggressivi e resistenti alle cure tradizionali.
Recenti studi hanno mostrato come, in molti tumori, ii) l’enzima AKR1C3 sia sovraregolato e contribuisca alla perdita di efficacia del chemioterapico e alla comparsa di resistenza; ii) la sua inibizione sensibilizzi le cellule tumorali ai chemioterapici (potenziando così, tramite un meccanismo sinergico, l’effetto della sola chemioterapia) e renda le cellule tumorali meno resistenti ai farmaci chemioterapici d’elezione e alla radioterapia. Negli ultimi anni il Dip. di Scienza e Tecnologia del Farmaco ha sviluppato efficaci e selettivi inibitori di AKR1C3 capaci di potenziare in cellule di tumore oro-faringe (OPSCC) e prostatico CRPC, l’effetto di alcuni farmaci di prima linea. Inoltre, ha da poco dimostrato la sovraregolazione di AKR1C3 anche in cellule di altri tumori maligni di alta letalità, quali il tumore mammario triplo-negativo (TNBC) e il colangiocarcinoma (CCA).
TORAK si propone:
1. Analizzare l'espressione di geni sovraregolati, tra cui AKR1C3, in tessuti tumorali di CCA , OPSCC, CRPC e TNBC prelevati da pazienti, disponibili presso la FEET. Il confronto dell’espressione genica in cellule tumorali sensibili e resistenti servirà per evidenziare ulteriormente il ruolo di AKR1C3 e di altri possibili geni nella perdita di sensibilità alle terapie standard e nel fenomeno della resistenza. Contemporaneamente dati di espressione di AKT1C3 presenti in dataset pubblici di questi tumori per pazienti trattati in Piemonte e nel mondo, verranno associati ai dati clinici, in particolare con la comparsa di recidive.
2. Sviluppare nuovi inibitori di AKR1C3 più potenti e selettivi, progettati e sintetizzati attraverso la green chemistry e cicli di ottimizzazione.
3. Studiare l’attività antitumorale degli inibitori di AKR1C3 già disponibili o di nuova sintesi, in associazione con terapie standard, in cellule CRPC, OPSCC, CCA e TNBC (cellule in adesione, organoidi e fettine organotipiche ottenuti da tessuti tumorali di pazienti) sensibili o resistenti ai chemioterapici d’elezione. Attraverso saggi farmacologici, si valuterà se la loro co-somministrazione con agenti chemioterapici potenzi l’effetto antiproliferativo e/o sia in grado di rendere le cellule tumorali meno resistenti agli stessi chemioterapici.
4. Organizzare un workshop su “Recidive, metastasi e resistenza alle terapie: nuove strategie terapeutiche più efficaci e durature” presso il DSTF per divulgare i risultati di TORAK e le più recenti innovazioni ottenute in campo terapeutico.
Cancer is a constantly growing disease with 377,000 new diagnoses estimated in 2021 only in Italy (AIOM-AIRTUM). According to the Piedmont Cancer Registry, 88 people receive a diagnosis of malignant tumor every day, with a prevalence of prostate cancers in men and breast cancers in women (triple-negative breast cancers are also on the rise). The most frequent cancers, such as breast and prostate cancers, are therefore associated with rare cancers that are difficult to treat due to the insufficient clinical trials present. Today, new diagnostic techniques and available therapies have increased survival, but for many aggressive cancers there is still a poor prognosis due to the scarcity of effective therapies and, often, for the onset of resistance to those present. There is a growing need, therefore, to develop more powerful therapies and, above all, to understand the mechanisms by which, often, cancer cells manage to survive and become resistant to therapies. Only in this way can the treatments be made effective and avoid the development of recurrences at a distance, very often more malignant and with fatal outcomes.
The collaboration between local research institutions is fundamental for Piedmont to always be at the forefront of cancer research and treatment. UniTO (DSTF, DSCB and DDC) adheres to the FEET Foundation of Biella to consolidate an already existing network of excellences in territorial research in the field of oncology and propose the TORAK project.
The project aims, therefore, to strengthen research in the field of oncology, developing more effective and lasting therapies against the most aggressive tumors and resistant to traditional treatments. Recent studies have shown that, in many cancers, i) the enzyme AKR1C3 is upregulated and contributes to the loss of effectiveness of chemotherapy and the appearance of resistance; ii) its inhibition sensitizes cancer cells to chemotherapy (thus enhancing, through a synergistic mechanism, the effect of chemotherapy alone) and makes cancer cells less resistant to chemotherapy drugs of choice and radiotherapy. In recent years, the Department of Drug Science and Technology has developed effective and selective AKR1C3 inhibitors capable of potentiating the effect of some first-line drugs in oropharynx cancer cells (OPSCC) and prostate CRPC. In addition, it has recently demonstrated the upregulation of AKR1C3 also in cells of other high-lethal malignant tumors, such as triple-negative breast cancer (TNBC) and cholangiocarcinoma (CCA).
TORAK aims:
1. To analyze the expression of upregulated genes, including AKR1C3, in tumor tissues of CCA, OPSCC, CRPC and TNBC taken from patients, available at the Feet. The comparison of gene expression in sensitive and resistant cancer cells will serve to further highlight the role of AKR1C3 and other possible genes in the loss of sensitivity to standard therapies and in the phenomenon of resistance. At the same time, the expression data of AKR1C3 present in public datasets of these tumors for patients treated in Piedmont and in the world, will be associated with clinical data, in particular the presence of relapses.
2. Develop new, more potent and selective AKR1C3 inhibitors, designed and synthesized through green chemistry and optimization cycles.
3. To study the antitumor activity of already available or newly synthesized AKR1C3 inhibitors, in combination with standard therapies, in CRPC, OPSCC, CCA and TNBC cells (adhesion cells, organoids and organotypic slices obtained from tumor tissues of patients) sensitive or resistant to chemotherapeutic agents of choice. Through pharmacological assays, it will be evaluated whether their co-administration with chemotherapeutic agents enhances the antiproliferative effect and / or is able to make cancer cells less resistant to the same chemotherapeutic agents.
4. Organize a workshop on "Relapses, metastases and resistance to therapies: new more effective and lasting therapeutic strategies" at the DSTF to disseminate the results of TORAK and the latest innovations obtained in the therapeutic field.
The collaboration between local research institutions is fundamental for Piedmont to always be at the forefront of cancer research and treatment. UniTO (DSTF, DSCB and DDC) adheres to the FEET Foundation of Biella to consolidate an already existing network of excellences in territorial research in the field of oncology and propose the TORAK project.
The project aims, therefore, to strengthen research in the field of oncology, developing more effective and lasting therapies against the most aggressive tumors and resistant to traditional treatments. Recent studies have shown that, in many cancers, i) the enzyme AKR1C3 is upregulated and contributes to the loss of effectiveness of chemotherapy and the appearance of resistance; ii) its inhibition sensitizes cancer cells to chemotherapy (thus enhancing, through a synergistic mechanism, the effect of chemotherapy alone) and makes cancer cells less resistant to chemotherapy drugs of choice and radiotherapy. In recent years, the Department of Drug Science and Technology has developed effective and selective AKR1C3 inhibitors capable of potentiating the effect of some first-line drugs in oropharynx cancer cells (OPSCC) and prostate CRPC. In addition, it has recently demonstrated the upregulation of AKR1C3 also in cells of other high-lethal malignant tumors, such as triple-negative breast cancer (TNBC) and cholangiocarcinoma (CCA).
TORAK aims:
1. To analyze the expression of upregulated genes, including AKR1C3, in tumor tissues of CCA, OPSCC, CRPC and TNBC taken from patients, available at the Feet. The comparison of gene expression in sensitive and resistant cancer cells will serve to further highlight the role of AKR1C3 and other possible genes in the loss of sensitivity to standard therapies and in the phenomenon of resistance. At the same time, the expression data of AKR1C3 present in public datasets of these tumors for patients treated in Piedmont and in the world, will be associated with clinical data, in particular the presence of relapses.
2. Develop new, more potent and selective AKR1C3 inhibitors, designed and synthesized through green chemistry and optimization cycles.
3. To study the antitumor activity of already available or newly synthesized AKR1C3 inhibitors, in combination with standard therapies, in CRPC, OPSCC, CCA and TNBC cells (adhesion cells, organoids and organotypic slices obtained from tumor tissues of patients) sensitive or resistant to chemotherapeutic agents of choice. Through pharmacological assays, it will be evaluated whether their co-administration with chemotherapeutic agents enhances the antiproliferative effect and / or is able to make cancer cells less resistant to the same chemotherapeutic agents.
4. Organize a workshop on "Relapses, metastases and resistance to therapies: new more effective and lasting therapeutic strategies" at the DSTF to disseminate the results of TORAK and the latest innovations obtained in the therapeutic field.