RAN GTPase Peptide

Opportunity

This opportunity is led by Dr. Mohammad Isreb and visiting Prof. Mohamed El- Tanani and is underpinned by a patent family which is focussed on the inhibition of Ran GTPase as a therapy for cancer treatment with a focus on a new treatment to combat chemotherapeutic resistance in triple negative and metastatic breast cancer.

Background

Ran GTPase (Ran) is a Ras-related protein involved in cell cycle regulation, nuclear-cytoplasmic transportation, and cell transformation and has been shown to play an important role in cancer cell survival and cancer progression. Cancer cells with mutations and abnormal expression in proto-oncogenes and suppressors correlate to activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways which are the most frequently dysregulated signalling pathways in cancers. These pathways have been shown to be more susceptible to Ran knockdown than normal cells.

Experimental disruption of the guanine nucleotide cycle by using Ran blockade peptides loaded nanoparticles prevents the generation of Ran by disruption of nucleotide binding with the guanine nucleotide-exchange factor RCC1, resulting in a dominant inhibitory effect on Ran formation. This resulted in suppressing tumorigenesis and metastasis both in vitro and in vivo in the case of breast and lung cancer (other publications have shown this effect in other cancers). The team has developed a Ran blockade peptide inhibitor (RAN IP) which is the subject of patent application GB1607593.9, currently in National Filings.

The problem

Breast cancer is the most common malignant tumour in women. Every year, 1.7 million people are diagnosed worldwide, and approximately half a million people die from this disease. Chemoresistance is a main cause of breast cancer-related death, as it results in recurrence and metastasis. Thus, overcoming this issue is critical to improving the prognosis of patients with breast cancer. Drug resistance can be divided into intrinsic resistance, acquired resistance, and multidrug resistance which is considered the most common.

Multidrug resistance (MDR) often leads to poor treatment and poor prognosis for solid tumours such as breast cancer through various molecular mechanisms. The response rate of metastatic breast cancer to first-line chemotherapy drugs is usually 30%–70%, but it is not persistent, drug resistance occurs in 6–10 months, resulting in treatment failure. The 5-year survival rate of patients with metastatic breast cancer is only 27%. Triple Negative Breast Cancer (TNBC) represents approximately 15-20% of all newly diagnosed breast cancers and is generally a more aggressive disease with a poorer prognosis and higher grade than other types accounting for 5% of all cancer-related deaths annually. The median overall survival (OS) for the disease is 10.2 months with current therapies, with a 5-year survival rate of c.65% for regional tumours and 11% for those that have spread to distant organs. Chemotherapy remains the standard of care for TNBC treatment, but unfortunately, patients frequently develop resistance.

Application

The current application of the technology is in the development of the co-delivery of a Ran inhibitory peptide (RAN IP) and doxorubicin using dual-loaded liposomal carriers to combat chemotherapeutic resistance in breast cancer cells.

Doxorubicin (DOX) is frequently used to treat solid tumours, but its use is limited by the risk of progressive, dose-dependent cardiomyopathy, and irreversible congestive heart failure. Its cytotoxic effect arises from inhibition of DNA topoisomerase causing cancer cell death by inducing DNA damage. Unfortunately, studies have linked poor prognosis during DOX treatment with increased multidrug resistance (MDR). Ran overexpression may help cancer cells resistance to DOX. It has been shown that Ran has an important role in DNA damage repair, thus introducing a RAN inhibitor will neutralize this effect and synergize the effect of DNA damage caused by DOX and, thus, increase cell apoptosis. In vitro results showed that DOX inhibited RAN expression in cells then after 24 hours RAN expression was upregulated hence cells are resisting the cytotoxic effect of DOX. Then after treating with RAN-IP, the RAN expression was downregulated again and this re-sensitize the cells to DOX.

Benefits

The in vivo results confirmed the enhanced anti-cancer activity of a double-loaded liposome by achieving 86%, 96%, and 98% tumour growth inhibition after treatment with doses of 1X, 2X and 3X. We envisage that Ran IP in combination with a cytotoxic agent such as DOX will re-sensitize chemo resistant tumours.

Toxicity examinations showed that a combined-drug delivery system was found to be safer to liver and kidney tissues when compared to the free DOX.