CN114681456A - Use of PLX3397 in the treatment of colorectal cancer - Google Patents

Use of PLX3397 in the treatment of colorectal cancer Download PDF

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Publication number
CN114681456A
CN114681456A CN202210170225.6A CN202210170225A CN114681456A CN 114681456 A CN114681456 A CN 114681456A CN 202210170225 A CN202210170225 A CN 202210170225A CN 114681456 A CN114681456 A CN 114681456A
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colorectal cancer
plx3397
medicament
treatment
cells
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CN202210170225.6A
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Inventor
李英杰
骆衍新
朱铭轩
白亮亮
彭绍勇
王小琳
禹汇川
刘晓霞
黄美近
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Sixth Affiliated Hospital of Sun Yat Sen University
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Sixth Affiliated Hospital of Sun Yat Sen University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Abstract

The invention belongs to the technical field of medicines, and particularly relates to application of PLX3397 in treatment of colorectal cancer, and the invention discloses new application of PLX3397, namely application in treatment of colorectal cancer. According to research, the PLX3397 oral administration can obviously inhibit malignant proliferation of the colorectal cancer subcutaneous transplantation tumor, can also obviously reduce liver metastasis of the colorectal cancer, and can play a combined synergistic effect when the PLX3397 and 5-FU are combined. The PLX3397 is suggested to be prepared into a medicament for treating colorectal cancer, or a medicament for inhibiting the proliferation of colorectal cancer cells, or a medicament for reducing the liver metastasis of the colorectal cancer cells. Meanwhile, PLX3397 has lower toxic and side effects when used for treating colorectal cancer, thereby providing a new way and a new direction for treating colorectal cancer and having important application value.

Description

Use of PLX3397 in the treatment of colorectal cancer
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of PLX3397 in treatment of colorectal cancer.
Background
Colorectal cancer (CRC) is one of the most common malignancies, with the third highest incidence among all malignancies. Because early screens such as enteroscopes are not high in popularity, more than 35% of patients have distant metastasis during initial diagnosis, the chance of radical excision is lost, and only systemic treatment can be selected to prolong the survival. Among them, chemotherapy is one of the standard treatment regimens for metastatic colorectal cancer (mCRC), and the commonly used chemotherapy regimen is mainly a two-or three-drug regimen based on 5-fluorouracil (5-fluorouracil, 5-FU), oxaliplatin or irinotecan, but the regimen is toxic and difficult to be tolerated, which makes the overall survival of chemotherapy difficult to break through again.
PD1/PD-L1 immunotherapy offers the promise of thorough treatment of tumors in many patients with CRC, but only microsatellite instability-high (MSI) CRC will respond to immunotherapy targeting PD-1/PD-L1, which accounts for only 13-15% of colon cancer patients, and even less than 5% in rectal cancer patients, while microsatellite stability (MSS) CRC accounts for over 90%. Colloquially, tumors with abundant T cell infiltration are often referred to as "hot tumors," and respond well to immunotherapies that regulate T cell function (e.g., PD-1/PD-L1 antibody); on the other hand, tumors with less T cell infiltration and more myeloid cell infiltration such as macrophages are "cold tumors" and have resistance to treatment with PD-1/PD-L1 antibody. The MSS subtype mCRC which accounts for more than 90 percent of the total CRC belongs to a typical 'cold tumor', and is the mCRC which is difficult to treat and has poor prognosis. Therefore, the development of a new high-efficiency and low-toxicity treatment scheme aiming at the subtype tumors is expected to bring welfare to mCRC patients.
The dense stroma of CRC solid tumors is rich in activated fibroblasts and tumor-associated macrophages (TAMs). TAMs infiltrated in tumors are important immune cells constituting the tumor microenvironment and participate in the regulation of various complex immune responses of tumors. TAM can be divided into two major categories, M1 and M2, M1 TAM has the main function of driving type 1T helper cell (Th1) reaction, and has cytotoxic activity to tumor cells; in contrast, M2 TAM produces anti-inflammatory response by secreting anti-inflammatory cytokines, participates in tumor angiogenesis and extracellular matrix remodeling, and controls inflammatory response by inhibiting M1 TAM mediated function and adaptive immunity, thereby occupying a dominant position in tumor microenvironment and promoting tumor progression. While the insensitivity of M2 TAM to chemotherapy or immunotherapy produces a non-negligible effect, the amount of infiltration is closely related to the prognosis of CRC patients, mainly expressed in the following two aspects: (1) m2 TAM can inhibit the activity of T cells in killing tumor, and help tumor escape from killing of immune system. Infiltrating M2 TAM in CRC liver metastases may inhibit immunotherapy by mediating depletion of T cells, resulting in poor prognosis. These macrophages can also help to form a physical barrier, inhibiting infiltration of T cells. (2) TAMs in the CRC tumor microenvironment also desensitize tumor cells from chemotherapeutic drugs. Therefore, based on the important role of TAM in CRC, targeting TAM is likely to be a new immunotherapy effective in treating such MSS-type mCRC.
Colony stimulating factor 1receptor (CSF 1R) is one of the most important targets of TAM. CSF1R belongs to type III receptor tyrosine kinase family, its signal transduction is crucial for macrophage differentiation and survival, and plays a key role in TAM to promote tumor progression and inhibit immunity, blocking CSF-1/CSF1R pathway has been proved to significantly reduce macrophage infiltration at tumor site, slow down primary tumor growth and reduce tumor metastasis. CSF1R was expressed differentially in different TAM subtypes, with the proliferation, differentiation and carcinogenic function of M2 TAM being dependent on CSF1R, but not M1 TAM. Therefore, specific inhibition of the survival, activation and function of M2 TAM by inhibition of CSF-1/CSF1R signaling may be an important strategy for immune-assisted treatment of CRC.
The first CSF 1R-targeting inhibitor pexidartinib (PLX3397, trade name: Turalio)) developed by the first three co-located companies of Japan pharmaceutical enterprises was approved by the US FDA in 2019 to be applied to clinical treatment of tenosynovitis megacytoma (TGCT), and has good curative effect and low toxic and side effects, but the application of the drug to mRC treatment has not been reported yet.
Disclosure of Invention
To overcome the above-mentioned deficiencies of the prior art, the present invention provides the use of PLX3397 in the treatment of colorectal cancer. The research of the invention finds that the PLX3397 oral administration can obviously inhibit the malignant proliferation of the colorectal cancer subcutaneous transplantation tumor and can also obviously reduce the liver metastasis of the colorectal cancer.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides application of PLX3397 in preparing a medicament for treating colorectal cancer.
Preferably, the colorectal cancer is an MSS subtype colorectal cancer.
More preferably, the colorectal cancer comprises advanced MSS subtype colorectal cancer.
The invention also provides application of PLX3397 in preparing a medicament for inhibiting colorectal cancer cell proliferation.
According to the invention, the CSF1R specific inhibitor has a remarkable inhibitory effect on proliferation of murine MSS subtype CRC cell CT26 subcutaneous transplanted tumor in vivo, and is dose-dependent. And PLX3397 is orally taken, and shows lower toxic and side effects in body weight indexes. The weight of the 5-FU is shown to be obviously stronger than that of PLX3397 by intraperitoneal injection of the 5-FU.
The invention also provides application of PLX3397 in preparing a medicament for reducing liver metastasis of colorectal cancer cells.
Preferably, the colorectal cancer cells include, but are not limited to, CT26 cells.
According to the research, the CSF1R specific inhibitor has an obvious curative effect on liver metastasis injected by CT26 cell spleen, and is equivalent to 5-FU.
The invention provides a medicament for treating colorectal cancer, which comprises PLX 3397.
The invention provides a medicament for treating colorectal cancer, which comprises PLX3397 and 5-fluorouracil.
According to the invention, the CSF1R specific inhibitor has a remarkable inhibitory effect on the proliferation of murine MSS CRC cell CT26 subcutaneous transplantation tumor in vivo, and is dose-dependent. And the combination of PLX3397 and 5-FU can play a role in combined synergism.
Preferably, a pharmaceutically acceptable carrier and/or excipient is also included. The composition is prepared by mixing PLX3397 or PLX3397 and 5-fluorouracil as main active ingredients with pharmaceutically acceptable carriers and/or excipients, and is prepared into clinically acceptable dosage forms.
Further, the excipient refers to diluents, binders, lubricants, disintegrants, cosolvent, stabilizers and other pharmaceutical matrixes which can be used in the pharmaceutical field.
Further, the carrier is a functional pharmaceutical adjuvant acceptable in the pharmaceutical field, and comprises a surfactant, a suspending agent, an emulsifier and some novel pharmaceutical high polymer materials, such as cyclodextrin, chitosan, polylactic acid (PLA), polyglycolic acid-polylactic acid copolymer (PLGA), hyaluronic acid and the like.
Preferably, the dosage form of the medicament includes, but is not limited to, injection, oral liquid, tablet, granule, capsule and pill. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if some drug is unstable under gastric conditions, may be formulated as enteric coated tablets.
Compared with the prior art, the invention has the beneficial effects that:
the invention discloses a new application of PLX3397, namely application in treating colorectal cancer. According to research, the PLX3397 oral administration can obviously inhibit malignant proliferation of the colorectal cancer subcutaneous transplantation tumor, can also obviously reduce liver metastasis of the colorectal cancer, and can play a combined synergistic effect when the PLX3397 and 5-FU are combined. It is suggested that PLX3397 can be prepared into a medicament for treating colorectal cancer, or a medicament for inhibiting proliferation of colorectal cancer cells, or a medicament for reducing liver metastasis of colorectal cancer cells. Meanwhile, PLX3397 has lower toxic and side effects when used for treating colorectal cancer, thereby providing a new way and a new direction for treating colorectal cancer and having important application value.
Drawings
Fig. 1 shows the inhibitory effect of PLX3397 or PLX3397 in combination with 5-FU on the growth of CT26 subcutaneous transplanted tumors [ a: in vivo imaging visualizations of PLX3397, 5-FU at different doses and Combination group (Combination) tumor-bearing mice; b: live imaging optical quantitative data; c: tumor volume; d: tumor weight; e: weight change in mice during dosing);
FIG. 2 shows that PLX3397 and 5-FU inhibit liver metastasis of CT26 cells (A: visualized liver metastasis live images of Vehicle, PLX3397 and 5-FU groups; B: representative live-shot images of liver tissues; C: optical quantification of live images; D: number of visible liver metastases; E: liver weight).
Detailed Description
The following further describes the embodiments of the present invention. It should be noted that the description of the embodiments is provided to help understanding of the present invention, but the present invention is not limited thereto. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
The experimental procedures in the following examples were carried out by conventional methods unless otherwise specified, and the test materials used in the following examples were commercially available by conventional methods unless otherwise specified.
EXAMPLE 1 therapeutic Effect of the CSF1R inhibitor PLX3397 on MSS subtype CRC
1. Experimental procedure
(1) Construction, administration and monitoring of MSS subtype CRC cell CT26 subcutaneous transplantation tumor
BALB/C mice (male, 6-8 weeks old, 20-25g in weight) were anesthetized with pentobarbital (50mg/kg), and then the inoculated sites on the backs of the mice were shaved, and each mouse was subcutaneously inoculated with 1X 106CT26 cells, when the tumor grows to about 100-150 mm3They were randomly divided into 5 groups [ 3 PLX3397 groups at different doses, 5-fluorouracil (5-fluorourail, 5-FU) control group, PLX3397 and 5-FU combination administration group ], 6-7 individuals per group ]. Wherein PLX3397 is dissolved in aqueous solution containing 5% DMSO and 25% PEG300 to prepare administration solution [ proper amount of PLX3397 powder is weighed, dissolved in DMSO (5% of the final volume), then PEG300 is added and mixed evenly (25% of the final volume), finally sterile water is added to prepare evenly dispersed emulsion, the stomach is irrigated by using an enema needle to administer the drug ], 5-FU is dissolved in water to prepare administration solution (proper amount of 5-FU powder is weighed, dissolved in sterile water according to dosage requirements to prepare clear solution, and the drug is injected into abdominal cavity to administer the drug). Each PLX3397 group of mice was orally administered (gavage) with different doses of PLX3397(0, 30, 60mg/kg) respectively, the control group was intraperitoneally injected with 5-FU (60mg/kg), the combination group was administered with PLX3397(60mg/kg, gavage) and 5-FU (60mg/kg, intraperitoneal injection) simultaneously every other day with a test period of 7 days, and the weight and tumor size of the mice were monitored during the test period. After the experiment, live body imaging is carried out, and finally, the mouse is euthanized, and the tumor is taken out and weighed.
(2) Construction, administration and monitoring of CT26 cell spleen injection liver transfer model
BALB/C mice (male, 6-8 weeks old, 20-25g in body weight) were anesthetized with pentobarbital sodium (50mg/kg) and injected 1X 10 per mouse spleen6CT26 cells were randomly divided into 3 groups (two PLX3397 groups, 5-FU control group) after 5 days, with 7 cells each. PLX3397 was dissolved in an aqueous solution containing 5% DMSO and 25% PEG300 to make a dosing solution, and 5-FU was dissolved in water to make a dosing solution. Each PLX3397 group of mice was orally administered (gavage) PLX3397(0, 60mg/kg), and the control group was intraperitoneally injected with 5-FU (60mg/kg), administered every other day, for 7 times. And (4) performing living body imaging at the test end point, finally euthanizing the mouse, weighing liver tissues, and taking a picture for recording.
2. Results of the experiment
As shown in fig. 1A-D, PLX3397 orally administered significantly inhibited the malignant proliferation of CT26 cell subcutaneous transplantable tumors and was dose dependent. Meanwhile, although the inhibition effect of PLX3397 with the same dose is weaker than that of 5-FU, the weight of mice is not obviously affected by PLX3397, but the weight of a 5-FU group is obviously reduced, which indicates that the tolerance of oral PLX3397 is better under the dose which achieves the effect similar to that of 5-FU injected into the abdominal cavity. In addition, the curative effect of the combination of PLX3397 and 5-FU is obviously better than that of a single medicine, and the combination has a synergistic effect.
Fig. 2A-E show that single dose oral administration of PLX3397 also significantly reduced liver metastasis from spleen-injected CT26 cells, with comparable effect to 5-FU, indicating therapeutic potential of PLX3397 in the late MSS subtype CRC.
The embodiments of the present invention have been described in detail, but the present invention is not limited to the described embodiments. It will be apparent to those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, and still fall within the scope of the invention.

Claims (10)

  1. Application of PLX3397 in preparing medicine for treating colorectal cancer.
  2. 2. Use according to claim 1, wherein the colorectal cancer is colorectal cancer of the MSS subtype.
  3. 3. The use according to claim 2, wherein the colorectal cancer comprises advanced MSS subtype colorectal cancer.
  4. Use of PLX3397 in the manufacture of a medicament for inhibiting proliferation of colorectal cancer cells.
  5. Application of PLX3397 in preparing a medicament for reducing liver metastasis of colorectal cancer cells.
  6. 6. Use according to claim 4 or 5, wherein said colorectal cancer cells include but are not limited to CT26 cells.
  7. 7. A medicament for the treatment of colorectal cancer, wherein the medicament comprises PLX 3397.
  8. 8. A medicament for the treatment of colorectal cancer, wherein the medicament comprises PLX3397 and 5-fluorouracil.
  9. 9. The medicament for treating colorectal cancer according to claim 7 or 8, further comprising a pharmaceutically acceptable carrier and/or excipient.
  10. 10. The drug for treating colorectal cancer according to claim 7 or 8, wherein the dosage form of the drug includes, but is not limited to, injection, oral liquid, tablet, granule, capsule, and pill.
CN202210170225.6A 2022-02-23 2022-02-23 Use of PLX3397 in the treatment of colorectal cancer Pending CN114681456A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109069512A (en) * 2016-04-01 2018-12-21 西格诺药品有限公司 Substituted adenine phosphate compound, its composition and related methods for the treatment of
WO2021170078A1 (en) * 2020-02-28 2021-09-02 上海润石医药科技有限公司 Use of csf-1r kinase inhibitor
CN113999221A (en) * 2021-11-04 2022-02-01 南京中医药大学 6-substituted indolone derivative, preparation method and medical application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109069512A (en) * 2016-04-01 2018-12-21 西格诺药品有限公司 Substituted adenine phosphate compound, its composition and related methods for the treatment of
WO2021170078A1 (en) * 2020-02-28 2021-09-02 上海润石医药科技有限公司 Use of csf-1r kinase inhibitor
CN113999221A (en) * 2021-11-04 2022-02-01 南京中医药大学 6-substituted indolone derivative, preparation method and medical application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MINGXUAN ZHU等: "Effect and mechanism of pexidartinib combined with chemotherapy in the treatment of KRAS and BRAF mutant MSS colorectal cancer", 2021年中国肿瘤标志物学术大会暨第十五届肿瘤标志物青年科学家论坛论文集, pages 423 - 424 *

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