Evaluation of a Promising New Combination of Protein Kinase Inhibitors on Organotypic Cultures of Human Renal Tumors

  • STATUS
    Recruiting
  • End date
    Sep 30, 2024
  • participants needed
    100
  • sponsor
    University Hospital, Grenoble
Updated on 23 January 2021
cancer
sunitinib
carcinoma
temsirolimus
ATM
pazopanib
nephrectomy
renal neoplasm
clear cell renal cell carcinoma

Summary

The investigators objective is to test the combination directly on organotypic cultures of tumors from patients after their excision in the Department of Urology and Renal Transplantation of the University Hospital of Grenoble and to compare their efficacy with that of currently selected treatments in the clinic.

The population targeted by the combination for use in clinical practice is patients with metastatic clear cell renal cell carcinoma.

Current treatments for these patients are Sunitinib, Pazopanib and Temsirolimus.

Description

Given the failure of conventional therapies in kidney cancer, both chemo and radio resistant, it was necessary to seek therapeutic alternatives.

Thus, in 2005, the first targeted therapies in kidney cancer came with protein kinase inhibitors including mTOR (mammilian target of rapamycin) inhibitors (Temsirolimus and Everolimus) and VEGFR inhibitors (Sunitinib, Sorafenib, Pazopanib and Axitinib).

Nevertheless resistance to these treatments appeared with their prolonged use as monotherapy in all cases. One of the main mechanisms of this therapeutic escape is the adaptation of the tumor cell via the use of an alternative pathway of deregulation of cell signaling.

Thus emerged the idea of simultaneously treating multiple targets to prevent the tumor cell from adapting. Phase I / II therapeutic trials have already been initiated with the combination of anti-BRAF (proto-oncogene B-Raf) and anti-MEK (MAP-ERK kinase) in metastatic melanoma or with the combination of anti-EGFR (epidermal growth factor receptor) and anti-MET in lung and breast cancer. The results are very promising since we observe a synergistic effect of two targeted therapies combined.

In kidney cancer, this escape phenomenon is also observed (example of the mTORC2 (mammilian target of rapamycin complex 2) crosstalk on AKT which limits the effect of mTORC1 (mammilian target of rapamycin complex 1) inhibitors at the level of the PI3 kinase signaling pathway).

It is therefore time to check if this strategy is applicable in kidney cancer. The investigators have, through a chemo-genomic screening of a hundred molecules stored in the CEA (French Alternative Energies and Atomic Energy Commission) chemical bank, found a combination of inhibitors targeting the kinases CK2 and ATM very effective on a human cell line of renal cell carcinoma clear. This combination has been tested on conventional cultures as well as on more innovative 3D cultures, better reproducing the tumor environment. The preliminary results obtained show that the combination is clearly more efficient in a 3D model as well as on the VHL-line (von Hippel-Lindau) in hypoxic condition, which is very encouraging.

In the context of preclinical validation, it is now essential to evaluate the therapeutic potential of these molecules by comparing their efficiency with those currently selected.

Details
Condition urinary tract neoplasm, Malignant neoplasm of kidney, Nephropathy, Kidney Disease (Pediatric), Kidney Cancer, Kidney Disease, Renal Cancer, Urologic Cancer, cancer, renal
Treatment Pazopanib, Sunitinib, Temsirolimus, CK2 and ATM inhibitors serine/ threonin Kinase combination
Clinical Study IdentifierNCT03571438
SponsorUniversity Hospital, Grenoble
Last Modified on23 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

major patient treated at the University Hospital of Grenoble for a renal tumor with suspected or confirmed malignancy.This includes non-metastatic patients undergoing renal lumpectomy, partial nephrectomy or total nephrectomy, as well as metastatic or locally advanced cancer patients undergoing cytoreductive surgery who are eligible for medical treatment at the same time

Exclusion Criteria

Contaminated patients with HIV and /or HBV (hepatitis B virus) and / or HCV (hepatitis C virus) positive serology
Absence or withdrawal of the informed consent of the patient
Tumors smaller than 2 cm on preoperative imaging
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