GRP78 Pathway Targeting In Cancer Treatment
27 Feb 2023
Phase 1Phase 2Clinical Result
The GRP78 protein belongs to the HSP70 family of heat shock proteins, which are involved in protein folding. According to cancer biopsy tissues, GRP78 expression is elevated in cancer cells, particularly in hypoxic tumors. Recent studies have also revealed that the protein plays additional roles in the development of cancer tumors. GRP78 does not stop there; it also gives cancer cells the capacity to resist off treatment. For the treatment of numerous diseases, including lung cancer, which causes the greatest number of cancer-related fatalities worldwide, GRP78-targeting has emerged as a possible therapeutic strategy. The protein has also been linked to conditions like COVID-19, where it has been demonstrated to aid the virus in invading the host cells, in addition to cancer. As a result, there is a great deal of therapeutic potential for GRP78 that has to be explored in order to treat disease.
Glucose-related protein 78 (GRP78) and other chaperones that are activated by glucose deficiency were discovered in the late 1970s. Stress has been one among the factors promoting its overexpression, albeit its expression varies depending on the tissue type, developmental stage, and stress conditions. Stressed cancer cells overexpress the protein, which travels from the plasma membrane where GRP78 is found to oncogenic pathways that help the tumor survive, grow, and invade. Depletion of glucose, poor blood flow, hypoxia and acidosis are a few stress factors that cause the excessive expression of GRP78, which builds up misfolded polypeptide chains in the endoplasmic reticulum. As a result, the ER transmembrane signal transducers PKR-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 release GRP78, which in turn initiates the unfolded protein response (ATF6). The ER transmembrane signal transducers strive to decrease the creation of polypeptide chains until the cellular equilibrium is achieved, whereas GRP78 acts in protein folding to preserve homeostasis.
Although homozygous GRP78 knockdown results in fetal mortality, it is clear from studies employing GRP78 knockout mice that GRP78 is crucial for embryogenesis. GRP78 heterozygosity resulted in prolonged delay and slowed tumour growth in a transgenic mice model of aggressive metastatic breast cancer Hence, GRP78 heterozygosity is a trustworthy resource for researching the role of GRP78 in the development of human disease. GRP78 has been discovered to have a crucial role in tumour growth, angiogenesis, aggressiveness, dissemination, and chemoresistance in cancer. While GRP78 expression in adult tissues is typically modest in the absence of stress, it is remarkably increased in cancer cells, solid tumors, and human tumor biopsies.
Recently, GRP78 was presented as a prostate cancer predictive marker and prospective treatment target. According to research by Fu et al., selective deletion of GRP78 in murine prostate epithelium eliminated prostate cancer and prevented AKT activation without affecting the growth or development of the prostate. If more research investigations are conducted, results from comparable studies imply that the inhibition/deletion/inactivation of GRP78 is a novel, distinct technique for preventing malignancies like prostate cancer in the future.
Only Bold Therapeutics and BiPER Therapeutics currently have candidates in the preclinical or clinical stages, according to the global clinical trials database. BOLD-100, a first-in-class clinical stage drug from Bold Therapeutics, is being used to treat advanced malignancies. In a phase I/II trial, it is being assessed in conjunction with FOLFOX for colorectal cancer, pancreatic cancer, gastric malignancies, cholangiocarcinoma, and esophageal squamous cell carcinoma. BOLD-100 phase II trials for multiple myeloma and bladder cancer in combination with other anti-cancer medications are also being planned. The flagship initiative of BiPER Therapeutics, however, is BPR001, a first-in-class small molecule that is now enabling for the IND and targets the GRP78.
Although it has serious side effects, chemotherapy is a hopeful treatment option for a number of cancers. Therefore, the creation of novel cancer treatment techniques is unavoidable. GRP78 is steadily becoming a popular topic in the field of cancer research. It is becoming more and more clearer how GRP78 affects the development, progression, and outcomes of different cancers. Having a better understanding of these processes may help us identify additional flaws in tumor cells, which will eventually lead to the creation of innovative treatment approaches. Drugs with innovative therapeutic effect-delivery mechanisms are urgently needed, and GRP78 inhibition is one of these, which has potential in changing the cancer treatment paradigm in the future.
Neeraj Chawla
Research Head
Kuick Research
neeraj@kuickresearch.com
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