CN111569078A

CN111569078A - Use of SIRT1 inhibitors for side effects caused by combination of VEGFR inhibitors and immune checkpoint inhibitors

Info

Publication number: CN111569078A
Application number: CN202010558434.9A
Authority: CN
Inventors: 刘文杰; 林微微
Original assignee: Shanghai Xinying Biotechnology Co ltd
Current assignee: Shanghai Xinying Biotechnology Co ltd
Priority date: 2020-06-18
Filing date: 2020-06-18
Publication date: 2020-08-25

Abstract

The invention belongs to the technical field of medicines, and relates to application of a SIRT1 inhibitor to side effects caused by combination of a VEGFR inhibitor and an immune checkpoint inhibitor, in particular to application of a SIRT1 inhibitor to prevention and/or treatment of side effects caused by combination of a VEGFR inhibitor and a PD-1/PD-L1 inhibitor. Compared with the prior art, the invention can solve the side effect caused by the drug combination of the VEGFR inhibitor and the PD-1/PD-L1 inhibitor.

Description

Use of SIRT1 inhibitors for side effects caused by combination of VEGFR inhibitors and immune checkpoint inhibitors

Technical Field

The invention belongs to the field of medicines, and relates to application of a SIRT1 inhibitor to side effects caused by combination of a VEGFR inhibitor and an immune checkpoint inhibitor, in particular to application of a SIRT1 inhibitor to prevention and/or treatment of side effects caused by combination of a VEGFR inhibitor and a PD-1/PD-L1 inhibitor.

Background

Cancer (Cancer) is caused by abnormal proliferation of cells. Current traditional methods of treating cancer include surgery, radiation therapy, chemotherapy immunotherapy, gene therapy, and the like. The reasons influencing the occurrence and development of the tumor are very complex, and drug resistance and tumor recurrence are easy to generate in the treatment process, so that the tumor treatment difficulty is higher.

An immune checkpoint inhibitor (PD-1/PD-L1 inhibitor) is a common anticancer drug, and the PD-1/PD-L1 inhibitor specifically recognizes and binds to PD-1 on the surface of lymphocytes, blocks a PD-1/PD-L1 signal channel, further activates the immune killing effect of T cells on tumors, mobilizes the immune system of an organism and eliminates in-vivo tumor cells. Common PD-1/PD-L1 inhibitors currently marketed globally include O, K, T, I, B, and Libtayo.

VEGFR inhibitors are anti-angiogenic drugs which change the microenvironment for tumor growth by inhibiting angiogenesis around tumor cells, reduce the nutrient acquisition of the tumor cells and finally achieve the purpose of treatment. At present, more than 10 targeted drugs aiming at VEGFR vascular inhibitors are approved and tested at home and abroad, mainly comprising small molecular tyrosinase inhibitors and monoclonal antibody inhibitors.

According to the report of the existing research results, the combined treatment of the anti-angiogenesis drug and the immune checkpoint inhibitor can obviously improve the curative effect compared with the single use of the anti-angiogenesis drug.

For example, chinese patent CN108601831B discloses the use of an anti-PD-1 antibody in combination with a VEGFR inhibitor for the preparation of a medicament for the treatment of cancer, which describes that adverse drug reactions mediated by anti-PD-1 antibodies and/or immunity are reduced when PD-1 antibodies are used in combination with a VEGFR inhibitor.

However, the combination therapy of the anti-angiogenesis drug and the immune checkpoint inhibitor has good curative effect and can cause a series of more serious side effects, such as hand-foot syndrome or hand-foot skin reaction. Such side effects seriously affect the quality of life of the patient.

At present, the pathogenesis of side effects (such as hand-foot syndrome or hand-foot skin reaction) caused by the combination treatment of the anti-angiogenesis drug and the immune checkpoint inhibitor is complex, some side effects are slightly different from those caused by a common VEGFR inhibitor single drug, and an effective treatment method for the side effects caused by the combination of the VEGFR and the PD-1/PD-L1 inhibitor drug does not exist in the prior art, so that the problem is urgently solved.

Disclosure of Invention

Aiming at the current situation that no side effect caused by the combination of a VEGFR inhibitor and a PD-1/PD-L1 inhibitor medicament is effectively treated in the market at present, the invention provides the application of the SIRT1 inhibitor in preventing and/or treating the side effect caused by the combination of the VEGFR inhibitor and the PD-1/PD-L1 inhibitor medicament.

The purpose of the invention can be realized by the following technical scheme:

in the first aspect of the present invention: provides the application of the SIRT1 inhibitor in the preparation of medicines for preventing and/or treating side effects caused by the combination of a VEGFR inhibitor and a PD-1/PD-L1 inhibitor medicine.

In one embodiment of the invention, the side effect caused by the combination of the VEGFR inhibitor and the PD-1/PD-L1 inhibitor mainly refers to hand-foot syndrome or hand-foot skin reaction caused by the combination of the VEGFR inhibitor and the PD-1/PD-L1 inhibitor.

Therefore, the invention further provides an application of the SIRT1 inhibitor in preparing a medicament for preventing and/or treating hand-foot syndrome or hand-foot skin reaction caused by the combination of a VEGFR inhibitor and a PD-1/PD-L1 inhibitor medicament.

In one embodiment of the invention, the SIRT1 inhibitor is selected from nicotinic acid, nicotinamide, and the like.

In one embodiment of the invention, the VEGFR inhibitor may also be a VEGF inhibitor, and the VEGFR inhibitor and/or VEGF inhibitor includes regorafenib, ponatinib, cabozantinib, Ramucirumab, Bevacizumab, lenvatinib, sorafenib, pazopanib, apatinib, axitinib, nidanib, vandetanib, sunitinib, tizovatinib, fanimitib, tertianib, semanib, polyviranib, doratinib, orantinib, vatatinib, teitinib, gletinib, dritinib, ilonasib, rebastiib, golstiib, foratinib, feitinib, taicinib, tainatinib, alitinib, chitina, and any pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable combination thereof.

In one embodiment of the invention, the PD-1/PD-L1 inhibitor is selected from the group consisting of Nivolumab, Pembrolizumab, Torpilimab, Sintilimab, camrelizumab, and the like.

Second aspect of the invention: provides a medicine for preventing and/or treating side effects caused by the combination of a VEGFR inhibitor and a PD-1/PD-L1 inhibitor, and the medicine takes a SIRT1 inhibitor as a medicinal component.

In one embodiment of the invention, in the medicament for preventing and/or treating the side effect caused by the combination of the VEGFR inhibitor and the PD-1/PD-L1 inhibitor medicament, the concentration of the SIRT1 inhibitor ranges from 0.001% (w/w) to 50% (w/w), preferably from 0.05% (w/w) to 10% (w/w), and for example, the concentration of 0.05% (w/w), 2% (w/w), 5% (w/w) or 10% (w/w) can be selected.

In one embodiment of the invention, the agent for preventing and/or treating the side effects caused by the combination of the VEGFR inhibitor and the PD-1/PD-L1 inhibitor is administered topically, and the dosage form is selected from ointment, gel, lotion or cream, preferably gel.

The gel matrix can be one or more of carbomer, gelatin, acacia, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, AVC, polyoxyethylene, etc.; the humectant can be one or more of glycerol, polyethylene glycol, sorbitol, propylene glycol, paraffin oil, mineral oil, squalane, silicone oil fatty alcohol, etc.; the skin penetration enhancer may be one or more of azone, dimethyl sulfoxide, propylene glycol, ethanol, etc.

The invention also provides a method for treating side effects caused by the combination of a VEGFR inhibitor and a PD-1/PD-L1 inhibitor, which comprises administering to a subject in need thereof an effective amount of a medicament containing a SIRT1 inhibitor as a pharmaceutical ingredient.

Compared with the prior art, the invention provides the application of the SIRT1 inhibitor in preventing and/or treating the side effect caused by the combination of the VEGFR inhibitor and the PD-1/PD-L1 inhibitor, and can solve the side effect caused by the combination of the VEGFR inhibitor and the PD-1/PD-L1 inhibitor.

Drawings

FIG. 1: photographs of the left, front and right paw of a rat model of the VEGF/VEGFR inhibitor + PD-1/PD-L1 inhibitor caused hand-foot syndrome.

FIG. 2: photographs of the left paw (coated with sirt1 inhibitor gel), the front and right paw (coated with blank gel) of a typical rat in the dosing group of examples 1-9 of the present application are shown.

FIG. 3: typical HE staining results of rats in the blank group (i.e., normal rat paw), VEGF/VEGFR inhibitor + PD-1/PD-L1 inhibitor (i.e., post-molding paw), VEGF/VEGFR inhibitor + PD-1/PD-L1 inhibitor + sirt1 inhibitor group (i.e., post-coated paw) in examples 1-9 of this application are shown.

Detailed Description

The invention is described in detail below with reference to the figures and specific embodiments.

Examples 1 to 11

The SIRT1 inhibitor can prevent/treat hand-foot syndrome caused by VEGF/VEGFR inhibitor and PD-1/PD-L1 inhibitor

Rat animal models were constructed by administering the VEGFR/VEGF inhibitors shown in table 1, intravenous infusion of pembrolizumab (5mg/kg) or nivolumab (10mg/kg) in aqueous solution on days 7,10, and 13, respectively, to SD rats of 8-week females by daily gavage, and several days later, the paw of the rat developed hand-foot syndrome symptoms (as shown in fig. 1). Similar to that in humans, rats develop symptoms of hand-foot syndrome after oral administration of the VEGF/VEGFR inhibitor + PD-1/PD-L1 inhibitor, and the symptoms are very similar. Thus, rats are very good animal models for mimicking the side effects (e.g., hand-foot syndrome) caused by VEGFR/VEGF inhibitor + PD-1/PD-L1 inhibitor.

After one week of acclimation, the rats (about 200g) were divided into groups of 10 rats each and subjected to a dosing test. Dissolution of VEGFR/VEGF inhibitors in castor oil: the mixed solution of ethanol 1:1, the amount of each intragastric administration is not more than 2mL, and the administration dose is shown in Table 1. 7,10,13 days, intravenous infusion of pembrolizumab (5mg/ml) or nivolumab (10mg/ml) in water was performed, after administration, rats were coated with SIRT1 inhibitor-containing gel (different concentrations, in w/w) on the left paw (paw and paw suture), rats were coated with blank matrigel as a blank, after application, the rats were fixed in a fixed cylinder for 4 hours, and after 4 hours, the rats were released, and the drug residues on the coated sites were wiped off with clear water, and the rats were returned to their cages. The dosing and smearing tests were repeated daily until the rats died or the test was over. After the administration of the drug for 15-18 days, the number of rats with the left paw kept normal or significantly lighter than the right paw symptoms was counted as the number of rats with effective inhibition of hand-foot syndrome.

Table 1 lists animal experimental combinations of VEGFR/VEGF inhibitor + PD-1/PD-L1 inhibitor and SIRT1 inhibitor, and corresponding experimental results (where the numerical value in the control rate column is the number of rats with hand-foot syndrome effectively inhibited per group/number of rats with hand-foot syndrome model established per group × 100%, the rate of establishing the hand-foot syndrome model per group is 60% to 80%, that is, about 6 to 8 rats in 10 rats have hand-foot syndrome models, and rats in different drug groups all have death or unsuccessful model in implementing the hand-foot syndrome model, etc.).

TABLE 1 Experimental conditions and results for examples 1-9

The results of Table 1 and FIGS. 2-3 indicate that SIRT1 inhibitors may be effective in alleviating hand-foot syndrome caused by VEGFR/VEGF inhibitor + PD-1/PD-L1 inhibitor. Meanwhile, from the H & E staining results shown in FIG. 3, the mouse claw cuticle of the VEGFR/VEGF inhibitor + PD-1/PD-L1 inhibitor group is obviously thickened compared with that of the blank control group, and the VEGFR/VEGF inhibitor + PD-1/PD-L1 inhibitor and SIRT1 inhibitor group shows that the claw cuticle thickening phenomenon can be reversed by locally coating a certain amount of SIRT1 inhibitor, namely, the hand-foot syndrome caused by the VEGFR/VEGF inhibitor + PD-1/PD-L1 inhibitor is relieved.

The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.

Claims

Use of a SIRT1 inhibitor for the manufacture of a medicament for the prevention and/or treatment of side effects caused by a combination of a VEGFR inhibitor and a PD-1/PD-L1 inhibitor.
2. The use of claim 1, wherein the side effects associated with the combination of the VEGFR inhibitor and the PD-1/PD-L1 inhibitor is hand-foot syndrome or hand-foot skin reaction associated with the combination of the VEGFR inhibitor and the PD-1/PD-L1 inhibitor.
3. The use of claim 1, wherein the use of the SIRT1 inhibitor for the preparation of a medicament for the prevention and/or treatment of hand-foot syndrome or hand-foot skin reactions caused by a combination of a VEGFR inhibitor and a PD-1/PD-L1 inhibitor.
4. The use of claim 1, wherein said SIRT1 inhibitor is selected from niacin and niacinamide.
5. The use of claim 1, wherein the VEGFR inhibitor is a VEGF inhibitor, and wherein the VEGFR inhibitor and/or VEGF inhibitor comprises regorafenib, ponatinib, cabozantinib, Ramucirumab, Bevacizumab, lenvatinib, sorafenib, pazopanib, Apatinib, axitinib, nidanib, vandetanib, sunitinib, tizovatinib, Famitinib, Tesevatinib, Vorolanib, Motesinib, Linafinib, Semaxanib, polyviranib, ornatinib, vatatinib, tiratinib, Glestatinib, Delitinib, Ilorasertib, Rebastinib, Golevatinib, Foretinfeb, getinib, Taatinib, Alatinib, Chiinanib, a pharmaceutically acceptable salt thereof, or a combination thereof.
6. The use of claim 1, wherein the PD-1/PD-L1 inhibitor is selected from the group consisting of Nivolumab, Pembrolizumab, toriplalimab, Sintilimab, camrelizumab.
7. A medicine for preventing and/or treating side effects caused by combination of a VEGFR inhibitor and a PD-1/PD-L1 inhibitor medicine takes a SIRT1 inhibitor as a medicinal component.
8. The medicament as claimed in claim 7, wherein the concentration of the SIRT1 inhibitor in the medicament for preventing and/or treating the side effects caused by the combination of the VEGFR inhibitor and the PD-1/PD-L1 inhibitor medicament is in the range of 0.001% (w/w) to 50% (w/w).
9. The medicament of claim 8, wherein the concentration of the SIRT1 inhibitor in the medicament for preventing and/or treating the side effects caused by the combination of the VEGFR inhibitor and the PD-1/PD-L1 inhibitor medicament is in the range of 0.05% (w/w) to 10% (w/w).
10. The medicament of claim 7, wherein the medicament for preventing and/or treating the side effects caused by the combination of the VEGFR inhibitor and the PD-1/PD-L1 inhibitor is administered topically, and the dosage form is selected from ointment, gel, lotion, and cream.