Better understanding of the Hippo pathway can possibly cure cancer: ASU researchers

Cancer is a leading cause of death globally and there are no current treatments available to efficiently treat the disease as the tumour is often diagnosed at a distant stage. Moreover, Cancer cells are often resistant to chemotherapy, radiotherapy and molecular-targeted therapy. Hippo signalling is a complex tumour suppressor, and its deregulation is a key feature in many cancers. The Hippo-signalling pathway regulates cell proliferation and organ size. The pathway takes its name from one of its key signalling components—the protein kinase Hippo. Greater understanding of Hippo pathway deregulation in cancers will be essential to guide the imminent use of Hippo-targeted therapies. We interviewed Dr. Najm to find out more…

You have done a specialisation in Cancer biology. Why did you pick Cancer as your area of specialisation?

I hold a PhD degree in Biochemistry from Jamia Hamdard in collaboration with Rajiv Gandhi Cancer Institute and Research Centre, New Delhi. I have previously worked as an Assistant Professor of Biotechnology at NIET, Greater Noida, Cancer Genetics Expert at Positive Bioscience based at Medanta Hospital, Consultant-Biology at an E learning company and Guest Faculty at Jamia Hamdard University. As I said, cancer has become a pandemic. We need to conduct more research studies to find better ways to detect and treat cancer. As the WHO says, when identified early, cancer is more likely to respond to treatment and can result in a greater probability of survival and less morbidity, as well as less expensive treatment.

Tell us about the key findings of your paper?

According to the World Health Organisation, Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. The dysregulated growth of cancer cells may be attributed to different mutations in the cancer related genes and examining these genes along with the associated pathways may assist in decreasing the burden of the disease in terms of treatment and survival time. The Hippo pathway was first discovered and linked to human cancers in the year 2002. It plays a crucial role in the majority of cancers, making it a censorious field for future investigation. Previous studies reveal that the role of the Hippo pathway remains the centre in the modulation of developmental biology. The mutated and altered gene expression of LATS1/2 (Large Tumour Suppressor kinase), MST1/2 (Member of Sterile-20 proteins kinase), and YAPs (Yes Associated Proteins), which are the chief factors of the Hippo pathway, basically promotes the invasion and migration of cancer cells. Therefore, targeting the hippo pathway genes is of utmost importance when considering new treatment strategies such as precision or personalised medicine.

So, a better understanding of the Hippo pathway can possibly cure Cancer?

Yes. Most Cancer patients have a combination of treatments, such as surgery with chemotherapy and/or radiation therapy. Sometimes, despite the best care cancer comes back. When this happens it is called a recurrence or relapse. We found out in various research findings that when targeted therapy drugs were administered to patients after analysing multiple genes involved in the Hippo signalling pathway, the patients responded efficiently to the treatment and there were no relapses. Targeted therapy or precision medicine is a cancer treatment that uses drugs to target specific genes and proteins that are involved in the growth of cancer cells. Thus, a better understanding of the Hippo pathway is essential to untangle tumour biology and to develop novel anticancer therapies. It has the potential to cure Cancer or at least increase the healthy life-span of a patient. 

Your PhD topic was related to Breast Cancer. Tell us more about it?

My PhD thesis title was ‘Molecular Analysis of CYP1A1, Prohibitin and p53 gene in North Indian Female Breast Cancer Patients’. Breast cancer is the most commonly diagnosed cancer among females, worldwide. Although earlier it was considered a disease of Western women, over half (52%) of new breast cancer cases and 62% of deaths occur now in developing countries. The understanding of these three genes is critical to the diagnosis of Breast Cancer.  The TP53 gene regulates cell division by keeping cells from growing and dividing (proliferating) too fast or in an uncontrolled way. Prohibitin also plays many critical roles in fundamental cellular processes, but not much research is done in India about its role in relation to Breast cancer. CYP1A1 helps in the secretion of drug residue stores in the body following cessation of use. I wanted to find out through Molecular Analysis of CYP1A1 whether or not drug residue is contributing to Breast cancer.

What did you find out in the study?

During the course of the study, I evaluated mutations (type of change in the DNA) in p53, CYP1A1 and Prohibitin gene. Further we compared the expression pattern (the process by which the information encoded in a gene is used to direct the assembly of a protein molecule) of p53, CYP1A1 and Prohibitin genes in Indian Female Breast Cancer Patients and normal individuals by Immunohistochemistry (IHC) and clinically correlated with the patients data. IHC is a special staining process performed on fresh or frozen breast cancer tissue removed during biopsy.

In the Prohibitin gene we observed significant Missense mutation, a genetic alteration in which a single base pair substitution alters the genetic code in a way that produces an amino acid that is different from the usual amino acid at that position. We also found a significant association between age and mutational status of the gene. In CYP1A1 gene five novel mutations were observed and were significantly linked with the stages of breast cancer. We did a mutational analysis of the p53 gene on the hot spot regions and did not find any mutation in the p53 gene in our case study. All these findings suggest the overbearing role of these genes in progression of breast cancer.

“Over the past few decades multiple studies have been carried out to get deep insight in understanding the numerous factors involved in Breast carcinogenesis. Though multiple alterations have been analysed by researchers to obtain better and effective treatment and diagnosis for combating Breast Cancer, there is still need for advanced understanding of the multiple factors which are directly or indirectly linked to the development of the disease. The need to study genetic alterations in different pathways and their association with each other is important to win the fight against cancer.”

–Dr. Mohammad Zeeshan Najm, Visiting Scientist at Apeejay Stya University