Table 2.

Proof of concept in animal models for therapeutic benefit of reduction of DNM2

Type of cancer	Animal model	Approach for DNM2 reduction	Read out	Reference
Prostate	Implantation of tumor cells (PC3, LNCaP, and C4-2) in prostate of male SCID mice	Stable expression of DNM2-siRNA or scrambled-siRNA in injected cells	9 weeks after cell injection:  • Decrease in tumor weight  • Reduction of number of lymph node metastases (for the PC3 cells able to induce metastases)	[36]
Prostate	Subcutaneous injection of PC3 cells in athymic mice	Pharmacological inhibitor (DBHA). Intratumoral injection in tumors of 7–13 mm	• Reduction of the tumor volume at day 4 and day 8 after injection (vs vehicle injected tumors)  • No apparent toxic effect at the necropsy (day 8)	[89]
Pancreas	Implantation of tumor cells overexpressing DNM2 or phospho-deficient DNM2 (PxPC-3) in pancreas of nude mice	Stable expression of WT DNM2-GFP or phospho-deficient DNM2-GFP in injected cells	2 weeks after cell injection:  • Comparable size of primary tumor  • Expression of the phospho-deficient mutant limits the distal dissemination of tumor cells from the injection area (vs WT DNM2-expressing cells) 8 weeks after cell injection:  • Similar volume of the primary pancreas tumors  • Large tumors in the body cavity  • Expression of the mutant DNM2 decrease the number of large intestinal tumors vs WT DNM2-expressing cells  • No liver tumors after injection of cells expressing the mutant (which occurs in 3 of 18 mice injected with cells overexpressing WT DNM2)	[42]
Breast	Injection of tumor cells expressing inducible DNM2 shRNA (MDA-MB-231-BR3) into mammary fat pads of nude mice	Doxycycline-inducible shRNA against DNM2 and control shRNA in injected cells	• No decrease in tumor volume alone  • Improvement of the tumor volume reduction induced by chemotherapy by cyclophosphamide	[41]
Glioblastoma	Injection of tumor cells (LN444/PDGF-A) into the brain of mice	DNM2-siRNA or control-siRNA in injected cells	8 weeks after cell injection:  • Suppression of the PDGFRα–stimulated glioma growth (tumor volume) and invasion (number of prodruded fingers from tumors)  • Decrease in tumor cell proliferation  • Increase in cell apoptosis	[60]
Glioblastoma	Injection of tumor cells (GSC#035 with stable expression of luciferase) into the brain of nude mice	Continuous release of a DNM2 inhibitor (CyDyn 4–36) for 14 days by subcutaneous osmotic minipumps once tumors were established	Luciferase in vivo imaging after 1, 4, 8, 11 and 14 days of treatment:  • Reduction of tumor volume statistically significant from 11 days of treatment (vs vehicle treated mice)	[82]
Leukemia	6-week-old Lmo2Tg mice	IP injection twice daily for 5 days on 2 consecutive weeks of a DNM2 inhibitor (Dynole 34–2)	After 2 weeks of treatment:  • Reduction in the number of DN3a thymocytes  • Decrease in pre-LSC frequency  • Progressive exhaustion of pre-LSCs In non-tumour-bearing control mice: no detrimental effect of treatment on differentiated cells in the thymus and the bone marrow or the number of phenotypic bone marrow stem and progenitor cells	[90]
Leukemia	Injection of immature (ETP12) and mature (ALL8) T-ALL cell lines in mice	IP injection twice daily for 5 days on 2 consecutive weeks of a DNM2 inhibitor (Dynole 34–2). Treatment started when the average proportion of leukemic cells in the peripheral blood reached 1%	• Increased survival of treated mice 24 h after the last administration:  • Reduction in leukemic cells in the peripheral blood, bone marrow and spleen  • Inhibition of the abnormally activated IL-7 and NOTCH1 signaling pathways in leukemic cells	[90]
Leukemia	Injection of AML cell lines AML01-307 and AML18) in immunodeficient mice	IP injection twice daily for 5 days on 2 consecutive weeks of a DNM2 inhibitor (Dynole 34–2)	• Delayed onset of the disease  • Increased survival of treated mice 24 h after the last administration:  • Inhibition of IL-3, GM-CSF and SCF signaling pathways in leukemic cells  • Less patient-derived AML cells in bone marrow and spleen of treated mice	[90]

AML Acute myeloid leukemia, C4-2 Androgen-resistant variant of the LNCaP cells, DBHA N-[4-(dipropylamino)benzylidene]-2-hydroxybenzohydrazide, DN3a thymocytes Population of T-cell progenitors (CD4⁻ CD8⁻ CD44⁻ CD25⁺ CD28^low) responsible for the preleukemic stem cells activity in the Lmo2^Tg mouse model of T-ALL, GSC#035 Glioma stem cell line, IP Intraperitoneal, Lmo2^Tg Cd2-Lmo2-transgenic mouse model of T-cell acute lymphoblastic leukemia (T-ALL), LN444/PDGF-A Glioblastoma cell line expressing PDGF-A, LNCaP Androgen-responsive prostate cancer cell line, MDA-MB-231-BR3 Triple-negative breast cancer cell line, PC3 Invasive and androgen receptor negative prostate cancer cell line, Phospho-deficient DNM2 Double mutant Tyrosine (231/597) Phenylalanine, Pre-LSC Preleukemic stem cells, PxPC-3 Pancreatic epithelial tumor cell line, SCID mice Severe combined immunodeficiency mice, siRNA Short interfering RNA inducing DNM2 reduction through RNA interference, WT Wild-type