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1. WO2020193740 - NEW STRATEGY FOR TREATING PANCREATIC CANCER

Publication Number WO/2020/193740
Publication Date 01.10.2020
International Application No. PCT/EP2020/058663
International Filing Date 27.03.2020
IPC
A61K 31/155 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
13Amines, e.g. amantadine
155Amidines , e.g. guanidine , isourea , isothiourea
A61K 31/513 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
495having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
513having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
A61K 31/7008 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
70Carbohydrates; Sugars; Derivatives thereof
7008Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
A61K 31/555 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
555containing heavy metals, e.g. hemin, hematin, melarsoprol
A61K 31/7068 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
70Carbohydrates; Sugars; Derivatives thereof
7042Compounds having saccharide radicals and heterocyclic rings
7052having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
706containing six-membered rings with nitrogen as a ring hetero atom
7064containing condensed or non-condensed pyrimidines
7068having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
A61K 31/4745 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
435having six-membered rings with one nitrogen as the only ring hetero atom
47Quinolines; Isoquinolines
4738ortho- or peri-condensed with heterocyclic ring systems
4745condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenanthrolines
CPC
A61K 31/155
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
13Amines
155Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
A61K 31/4745
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
435having six-membered rings with one nitrogen as the only ring hetero atom
47Quinolines; Isoquinolines
4738ortho- or peri-condensed with heterocyclic ring systems
4745condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
A61K 31/513
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
495having six-membered rings with two ; or more; nitrogen atoms as the only ring heteroatoms, e.g. piperazine ; or tetrazines
505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
513having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
A61K 31/519
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
495having six-membered rings with two ; or more; nitrogen atoms as the only ring heteroatoms, e.g. piperazine ; or tetrazines
505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
519ortho- or peri-condensed with heterocyclic rings
A61K 31/555
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
555containing heavy metals, e.g. hemin, hematin, melarsoprol
A61K 31/7068
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
70Carbohydrates; Sugars; Derivatives thereof
7042Compounds having saccharide radicals and heterocyclic rings
7052having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
706containing six-membered rings with nitrogen as a ring hetero atom
7064containing condensed or non-condensed pyrimidines
7068having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
Applicants
  • INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE) [FR]/[FR]
  • UNIVERSITÉ D'AIX MARSEILLE [FR]/[FR]
  • CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS) [FR]/[FR]
  • INSTITUT JEAN PAOLI & IRENE CALMETTES [FR]/[FR]
Inventors
  • CARRIER, Alice
  • MASOUD, Rawand
Agents
  • INSERM TRANSFERT
Priority Data
19305404.628.03.2019EP
Publication Language English (EN)
Filing Language English (EN)
Designated States
Title
(EN) NEW STRATEGY FOR TREATING PANCREATIC CANCER
(FR) NOUVELLE STRATÉGIE DE TRAITEMENT DU CANCER DU PANCRÉAS
Abstract
(EN)
The present invention relates to the treatment of pancreatic cancer. In this work, the inventors assess whether mitochondrial features heterogeneity in between PDAC patients could be used to refine their stratification and develop novel targeted cancer therapies. Through a functional analysis (Seahorse), they demonstrate that human pancreatic cancer cells have fully functional mitochondrial respiration (OXPHOS). Furthermore, they show that OXPHOS in PDAC cells is able to generate most of their ATP, thus refuting the well-established belief that ATP production by glycolysis predominates over OXPHOS in PDAC. Importantly, their study provides the demonstration that PDAC tumors can be stratified according to their energetic metabolism. Moreover, they show a correlation between OXPHOS rate and abundance of mitochondrial respiratory Complex I both at mRNA and protein level. Finally, they show a synergy of Phenformin treatment with standard chemotherapy (Gemcitabine) specifically for high OXPHOS patient cells. Thus the invention relates to an inhibitor of the mitochondrial respiration for use in the treatment of pancreatic cancer in a patient in need thereof. Particularly the patient has a high OXPHOS.
(FR)
La présente invention concerne le traitement du cancer du pancréas. Dans ce travail, les inventeurs ont évalué si l'hétérogénéité des caractéristiques mitochondriales entre les patients atteint d'adénocarcinome canalaire pancréatique (PDAC) pouvait être utilisée pour affiner leur classification et développer de nouvelles thérapies ciblées anticancéreuses. Par l'intermédiaire d'une analyse fonctionnelle (Seahorse), ils ont démontré que les cellules du cancer du pancréas humain ont une respiration mitochondriale complètement fonctionnelle (OXPHOS). En outre, ils ont montré que l'OXPHOS dans les cellules de PDAC était capable de générer la majeure partie de leur ATP, réfutant ainsi la croyance bien établie que la production d'ATP par glycolyse prédominait sur celle par OXPHOS dans le PDAC. De manière importante, leur étude fournit la démonstration que les tumeurs de type PDAC peuvent être classées en fonction de leur métabolisme énergétique. De plus, ils ont montré qu'il existait une corrélation entre le taux d'OXPHOS et l'abondance du complexe I de la chaîne respiratoire mitochondriale, aussi bien au niveau de l'ARNm que des protéines. Enfin, ils ont montré l'existence d'une synergie entre un traitement par la phenformine et la chimiothérapie standard (Gemcitabine) en particulier dans le cas des cellules de patients à OXPHOS élevée. Ainsi, l'invention concerne un inhibiteur de la respiration mitochondriale destiné à être utilisé dans le traitement du cancer du pancréas chez le patient le nécessitant. En particulier, le patient présente une OXPHOS élevée.
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