CN-121177511-B - Application of IMMU-132 and GSK2606414 in preparation of anti-colorectal cancer drugs and related drugs

Abstract

The invention discloses an application of IMMU-132 and GSK2606414 in preparation of anti-colorectal cancer drugs and related drugs, belonging to the technical field of biological medicines. IMMU-132 in synergistic combination with GSK2606414 inhibits WNT signaling pathway activity by down-regulating PERK-eIF2 alpha signaling axis, thereby preventing tumor cell growth and metastasis. The invention provides the synergy of IMMU-132 and GSK2606414, and through the dual regulation of UPR signal path and WNT signal path, PERK-eIF2 alpha signal axis is regulated, WNT signal path activity is inhibited, obvious synergistic anti-tumor effect is shown, a new strategy direction is provided for colorectal cancer treatment, and treatment selection with clinical transformation potential is provided for TROP2 positive colorectal cancer patients.

Inventors

• ZHANG SHUYONG
• LIU JIE
• LI MEI
• HUANG JIANMING

Assignees

• 赣南医科大学

Dates

Publication Date

20260508

Application Date

20251105

Claims (5)

1. 1. Use of a formulation comprising IMMU-132 and GSK2606414 for the manufacture of an anti-colorectal cancer medicament, characterized in that: ① At a cellular level, the concentration of IMMU-132 is 0.3-10 μg/mL, and the concentration of GSK2606414 is 0.3-10 μM; ② At animal level, IMMU-132 concentration was 2.5mg/kg and GSK2606414 concentration was 50mg/kg.
2. 2. Use of an antibody drug conjugate IMMU-132 in combination with a PERK inhibitor GSK2606414 for the preparation of an anti-colorectal cancer drug, characterized in that: In the application process, the water-soluble polymer is prepared, ① At a cellular level, the concentration of IMMU-132 is 0.3-10 μg/mL, and the concentration of GSK2606414 is 0.3-10 μM; ② At animal level, IMMU-132 concentration was 2.5mg/kg and GSK2606414 concentration was 50mg/kg.
3. 3. The use of claim 2, wherein IMMU-132 in synergistic combination with GSK2606414 inhibits WNT signaling pathway activity by down-regulating the PERK-eif2α signaling axis, thereby inhibiting tumor cell growth and metastasis.
4. 4. An anti-colorectal cancer drug is characterized in that the active ingredients of the drug are an antibody drug conjugate IMMU-132 targeting a TROP2 pathway and a PERK inhibitor GSK2606414 targeting a PERK signal pathway; ① At a cellular level, the concentration of IMMU-132 is 0.3-10 μg/mL, and the concentration of GSK2606414 is 0.3-10 μM; ② At animal level, IMMU-132 concentration was 2.5mg/kg and GSK2606414 concentration was 50mg/kg.
5. 5. The medicament of claim 4, wherein the anti-tumor medicament further comprises pharmaceutically acceptable excipients.

Description

Application of IMMU-132 and GSK2606414 in preparation of anti-colorectal cancer drugs and related drugs Technical Field The invention belongs to the field of biological medicine, and particularly relates to application of IMMU-132 and GSK2606414 in preparation of anti-colorectal cancer medicines and related medicines. Background Colorectal cancer is a prostate malignancy with both morbidity and mortality worldwide, and clinical treatment presents a significant challenge. Currently, the main treatment means include surgery, radiotherapy, chemotherapy, molecular targeted therapies (such as anti-VEGF/EGFR drugs), immune checkpoint inhibitors and the like. Although fluoropyrimidine-based chemotherapy regimens (e.g., FOLFOX, FOLFIRI) in combination with targeted drugs have become the standard therapy for metastatic colorectal cancer, most patients still face problems of limited therapeutic response rate, susceptibility to drug resistance, and recurrent tumor metastasis. The curative effect of the existing medicine is still unsatisfactory, and especially for the late patients, the prognosis improving effect is still insufficient. Therefore, the development of effective therapeutic drugs acting on new targets and having new mechanisms remains a critical problem to be solved in current clinical research of colorectal cancer. The antibody coupling medicine (ADC) couples the high-activity cytotoxicity medicine to the targeting antibody through a linker to form a biological missile capable of specifically targeting the tumor, so that the systemic toxicity is reduced while strong killing is realized, and the biological missile has become an important direction for cancer treatment. Currently, ten more ADC drugs are available worldwide and are used for treating various malignant tumors such as leukemia, lymphoma and breast cancer, however, in the colorectal cancer treatment field, no ADC drugs are successfully marketed yet, and the research and development of the target point of the existing ADC drugs are serious in homogeneity. Therefore, aiming at colorectal cancer, namely a high malignant tumor, the ADC target point with a brand-new action mechanism and corresponding medicaments are explored, and the method has great significance in breaking through the existing treatment bottleneck and meeting the urgent clinical demands. Trophoblast surface antigen 2 (TROP 2) is a transmembrane glycoprotein highly expressed in a variety of epithelial-derived tumors, and its overexpression is closely related to tumor progression, invasion and poor prognosis, and has become an important flood target. Targeting TROP2-ADC (IMMU-132) has been approved for the treatment of triple negative breast and urothelial cancers, which exert potent anti-tumor effects by targeted delivery of topoisomerase I inhibitor SN-38 to tumor cells. However, the potential of IMMU-132 for use in colorectal cancer treatment has not been fully revealed and its specific mechanism of action remains to be elucidated. In addition, the single drug treatment causes drug resistance problem, and further improvement of the clinical curative effect is limited. Therefore, the therapeutic effect and molecular mechanism of IMMU-132 in colorectal cancer are deeply explored, and the method has important significance for expanding the indication and optimizing the therapeutic strategy. Unfolded Protein Response (UPR) is a core signal network of cells that responds to endogenous and exogenous stress, maintaining protein homeostasis, whose sustained activation is closely related to tumor progression and therapeutic tolerance. In the key branch of UPR, activation of the PERK-eif2α -ATF4 signaling axis plays a central role in regulating cell stress adaptation and fate decisions. The prior study shows that the intervention of PERK-eIF2 alpha-ATF 4 signal axis can effectively enhance the sensitivity of cancer cells to chemotherapy and targeted drugs, and becomes a potential strategy for improving the anti-tumor curative effect. However, the specific role and control mechanism of this signaling axis in the response of colorectal cancer to TROP2-ADC drug IMMU-132 is currently unknown. Disclosure of Invention In order to solve the technical problems, the invention provides application of IMMU-132 and GSK2606414 in preparing anti-colorectal cancer drugs and related drugs, wherein the TROP2-ADC drug IMMU-132 can inhibit PERK-eIF2 alpha-ATF 4 signal axis by regulating unfolded protein reaction in colorectal cancer treatment, thereby inhibiting tumor growth, and further verifies the combined drug administration scheme of IMMU-132 and PERK inhibitor GSK2606414, which shows remarkable synergistic anti-tumor effect in external and internal models, and provides a new strategy direction for colorectal cancer treatment. In order to achieve the aim, the invention provides application of a preparation targeting TROP2 positive expression and/or PERK signal pathway in preparing an anti-colorectal canc