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Development of radiotracers for targeted radionuclide therapy of melanoma

ABG-120556 Thesis topic
2024-02-21 Public funding alone (i.e. government, region, European, international organization research grant)
UMR 1240 INSERM UCA (IMoST)
Clermont-Ferrand - Auvergne-Rhône-Alpes - France
Development of radiotracers for targeted radionuclide therapy of melanoma
  • Chemistry
  • Biology
  • Health, human and veterinary medicine
Organic chemistry, radiochemistry, medicinal chemistry, targeted radionuclide therapy, cancer, melanoma

Topic description

Despite recent advances in immunotherapy treatments, metastatic melanoma remains associated with poor prognosis. We previously reported the development of a small molecule, called ICF01012 and targeting melanin pigments, that has been radiolabelled with iodine-131 and evaluated for targeted radionuclide therapy (TRT) of pigmented melanoma in several preclinical models. The significant antitumour effects observed with this [131I]ICF01012 treatment prompted us to start an ongoing phase I clinical study (NCT03784625). However, the regulatory constraints for the radiosynthesis and handling of such iodine radionuclides and associated radiotracers as well as the clinical management of patients receiving high dose of [131I]ICF01012 encourage us to further investigate a second generation of melanin-targeted ligands radiolabelled with less restrictive metallic radionuclides for TRT (e.g. copper-67, lutetium-177 and et terbium-161 (beta--emitters) or actinium-225 (alpha-emitter)). The recruited PhD student will be in charge of the synthesis and characterization of ICF01012 analogues conjugated with polyazamacrocycles for metal radionuclide chelation. He/she will optimize the radiolabelling procedures and will participate to the preclinical evaluation of the radiotracers including stability and selectivity studies, cellular uptake, biodistribution and antitumour efficacy experiments in relevant mice models. This research project, part of the SIRIC LYriCAN+ program, will take benefit from the complementary and multidisciplinary expertise in radiopharmaceutical development of the IMoST (Clermont-Fd) and LAGEPP (Lyon) laboratories.

 

References: [1] Thivat E, Rouanet J, Auzeloux P, Sas N, Jouberton E, Levesque S, Billoux T, Mansard S, Molnar I, Chanchou M, Fois G, Maigne L, Chezal JM, Miot-Noirault E, D'Incan M, Durando X, Cachin F. Phase I study of [131I]ICF01012, a targeted radionuclide therapy, in metastatic melanoma: MELRIV-1 protocol. BMC Cancer 2022, 22(1):417. doi: 10.1186/s12885-022-09495-3.

 

[2] Parat A, Kryza D, Degoul F, Taleb J, Viallard C, Janier M, Garofalo A, Bonazza P, Heinric-Balard L, Cohen R, Miot-Noirault E, Chezal JM, Billotey C, Felder-Flesch D. Radiolabeled dendritic probes as tools for high in vivo tumor targeting: application to melanoma. J Mater Chem B 2015 3(12):2560-71. doi: 10.1039/c5tb00235d.

 

[3] Maisonial A, Kuhnast B, Papon J, Boisgard R, Bayle M, Vidal A, Auzeloux P, Rbah L, Bonnet-Duquennoy M, Miot-Noirault E, Galmier MJ, Borel M, Askienazy S, Dollé F, Tavitian B, Madelmont JC, Moins N, Chezal JM. Single photon emission computed tomography/positron emission tomography imaging and targeted radionuclide therapy of melanoma: new multimodal fluorinated and iodinated radiotracers. J Med Chem 2011, 54(8):2745-66. doi: 10.1021/jm101574q.

 

[4] Chezal JM, Papon J, Labarre P, Lartigue C, Galmier MJ, Decombat C, Chavignon O, Maublant J, Teulade JC, Madelmont JC, Moins N. Evaluation of radiolabeled (hetero)aromatic analogues of N-(2-diethylaminoethyl)-4-iodobenzamide for imaging and targeted radionuclide therapy of melanoma. J Med Chem 2008, 51(11):3133-44. doi: 10.1021/jm701424g.

Starting date

2024-09-01

Funding category

Public funding alone (i.e. government, region, European, international organization research grant)

Funding further details

French National Cancer institute (INCA), SIRIC LYriCAN+ program

Presentation of host institution and host laboratory

UMR 1240 INSERM UCA (IMoST)

The research unit IMoST (UMR 1240, INSERM, UCA) of Clermont-Ferrand, attached to ITMO « Technologies pour la Santé » and to the cancéropôle CLARA, aims at identifying new tools and/or targets for the treatment, the therapeutic follow-up and their transfer to clinical trials, essentially in the field of oncology. Relying on a strong expertise in radiolabeling and biomarker studies for treatment response and/or resistance, this unit is organized around two teams working on interconnected projects focused on 3 axis, melanoma, cartilage and triple negative breast cancer (TNBC).

In fine, the two teams will converge to personalized treatment approaches combining the identification and the highlight of biomarkers (imaging, biopathology) with associated therapies (vectorized therapies and internal radiotherapies). This approach is reinforced by the presence in the unit of a technical platform including locals and equipments dedicated to chemistry, radiochemistry, genomic/post-genomic (transcriptome, proteome, metabolome,…), experimental pharmacology and small animal in vivo imaging (SPECT, PET, optical imaging and X-ray). Our research works, as well as transfer to clinical trials, also benefit from the expertise of radiopharmacists, anatomopathologists, clinicians and oncologists of the Regional Center of Cancer Jean Perrin and the University Hospital Center Gabriel Montpied.

PhD title

Doctorat de chimie

Country where you obtained your PhD

France

Institution awarding doctoral degree

Université Clermont Auvergne

Graduate school

Ecole doctorale des sciences fondamentales

Candidate's profile

We are looking for a highly motivated candidate having the desire to work on a multidisciplinary research topic at the interface of organic chemistry/radiochemistry and biology. The candidate must have a master degree (or equivalent) in chemistry. A solid knowledge in organic chemistry (experimental and theorical) and in classical purification and analysis procedures (HPLC, flash chromatography, NMR, mass spectroscopy, …) is mandatory. Experience in radiochemistry will also be an asset. A good level (written/spoken) of English will be essential. In addition, a mobility between Clermont-Fd and Lyon research sites is asked.

 

2024-06-30
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