Dr. Rania Habib (Host): ​This is Transformational Pediatrics with Children's Mercy, Kansas City. I'm your host, Dr. Rania Habib. Joining me today is Dr. Tomoo Iwakuma, the Director of Translational Hematology Oncology Research at Children's Mercy, Kansas City. His research focuses on dissecting the mechanism of cancer progression. And today, we are discussing his recent research findings on the p53 gene.

Welcome to the podcast, Dr. Iwakuma. We're so excited to learn more about your research.

Dr. Tomoo Iwakuma: Thank you very much. Thank you for inviting me. I'm very excited about discussing about my research.

Host: Now, you are obviously on the cutting edge of cancer research. Let's start with the review of the p53 gene. What is it and what does it do?

Dr. Tomoo Iwakuma: p53 is actually the most of famous tumor suppressor genes. It's biochemically transcription factor, which binds DNA and transactivates numerous downstream gene involving cell cycle arrest, cell deaths, thereby functioning as a tumor suppressor.

Host: Okay, and where's it located?

Dr. Tomoo Iwakuma: It's chromosomal 17 in the human genome.

Host: Now, obviously, your research focuses on cancer progression, and you have some recent findings on the p53 gene. Can you give us a high level overview of your research and your findings?

Dr. Tomoo Iwakuma: Of course. My research, as I said, focusing on the tumor suppressor p53. The tumor suppressor p53 is the most frequently mutated gene in human cancer. And then, interestingly, most of the mutations are one amino acid change in the p53 proteins. This means mutant p53 protein is present in the cell.

And in the research has demonstrated that mutant p53 function as an oncogene instead of tumor suppressor and enhanced cancer spreading, which is metastasis as well as drug resistance, thereby making disease outcome worse. That is the center of my research.

Host: Wow. So, one amino acid change is essentially contributing to the p53 mutation, basically turning it from a tumor suppressor gene into an oncologic gene. Is that what I'm understanding?

Dr. Tomoo Iwakuma: Yes. However, our recent study have revealed that tumors with mutant p53 could be rather sensitive to the endoplasmic reticulum stress, so-called ER stress and ER stress-inducing chemotherapy drug called sorafenib.

Host: Wow, that's exciting.

Dr. Tomoo Iwakuma: Yes. We also addressed underlying mechanism in which the mutant p53 inhibit formation of the ER stress-mediated stress granule. Stress granule is intracellular aggregates comprising of the RNA and protein, and that are known to contribute to drug resistance. So by inhibiting this stress granule formation, mutant p53 sensitize cancer cells to the ER stress. That's what we found.

Host: Wow, that is so exciting. Now, as I understand these findings were very unexpected. Explain how you found it and the implications of these unexpected findings. 

Dr. Tomoo Iwakuma: Yeah. Since the mutant p53 is generally correlated with poor overall survival of the cancer patient, we take advantage of the commonly available database, public database. It's called The Cancer Genome ATLAS, TCGA. Using this database, we performed the overall survival analysis in the different cancer types, including colon cancer, breast cancer, and ovarian cancer.

Then, generally, most of the cancer type, mutant p53's presence is correlated with bad prognosis, which you can expect because mutant p53 functions as a oncogene. However, what we found is only in liver cancer cases, presence of the mutant p53 is correlated with better overall survival, compared to the liver cell, liver tumor, known for p53. This was surprising.

Host: Very surprising, because you would've thought it was the opposite.

Dr. Tomoo Iwakuma: Exactly.

Host: So, Dr. Iwakuma, what patient populations can benefit now from these findings? How many patients do you estimate could actually be impacted?

Dr. Tomoo Iwakuma: So given that mutant p53 can inhibit ER stress induced stress granule formations, and mutant p53 is the most frequently mutated gene in human cancer. So, our finding can benefit any patient with many types of cancer with p53 mutations. This could represent approximately 20-50% of the human cancer patients, depending on the cancer types and depending on the ability of the cancer cell to form the stress granules.

Host: That's impressive. Twenty to 50%, you said, of all cancer patients. That's amazing. Now, do you think that this would benefit both adult and pediatric patients?

Dr. Tomoo Iwakuma: Absolutely. That's what is exciting. We initially focus on the liver cancer. However, since we found this new mechanism, mutant p53 inhibit the stress granule, even adult cancer, this can be applicable. Our finding can be used for the adult cancer.

Host: This is exciting research. So, Dr. Iwakuma, what are the future science prescribing or policy implications of the findings of your research?

Dr. Tomoo Iwakuma: So, liver tumor and even other type of cancer with p53 mutations can be treated with ER stress-inducing anti-cancer drug. For example, the sorafenib. However, there's not much ER stress-inducing chemotherapy drugs. Therefore, a new anti-cancer drug that specifically induce ER stress need to be developed for future purpose.

Host: That's going to be really exciting. So, what's next for this research? Do you expect to do more on this topic or expand it to similar to topics?

Dr. Tomoo Iwakuma: Absolutely. Obviously, the more studies are required to determine which specific type of p53 mutations can inhibit stress granule formations. And also, we need to determine which type of cancer with p53 mutations can be treated by ER stress-inducing chemotherapy drugs. So, what we found is a weak point caused by mutant p53. So, we believe there are other weak points caused by mutant p53, which should be determined.

Host: That's amazing. So for your specific lab, are you going to continue to focus on just liver cancer patients or do you plan to expand now to other areas of cancer?

Dr. Tomoo Iwakuma: Yes. We are thinking of expanding the many type of cancers, and also we want to find out that any FDA-approved drug could cause other ER stress or not.

Host: That's very exciting. So, Dr. Iwakuma, what is your final take-home message for the audience? You have provided us a wonderful overview of your research, how it can translate to helping to hopefully cure cancer one day. So, what's your final take home message? 

Dr. Tomoo Iwakuma: Everybody thinks mutant p53 is oncogene and it makes cancer worse. However, in the meantime, it can code some weak point as well. Because of the cancer cell expressing this bad oncogene mutant p53, cancer cells may have other weak points caused by this mutant p53, which should be identified in the future. And this weak point can be targeted as a cancer cell.

Host: That's such an amazing finding, and we're really looking forward to seeing how your research really changes the entire world and face of cancer and cancer treatment.

Dr. Tomoo Iwakuma: Thank you very much. 

Host: Once again, that was Dr. Iwakuma, the Director of Translational Hematology Oncology Research at Children's Mercy, Kansas City. To refer your patient or for more information, please visit childrensmercy.org to get connected with one of our providers. I'm your host, Dr. Rania Habib. Wishing you well.

This has been Transformational Pediatrics with Children's Mercy, Kansas City. Please remember to subscribe, rate, and review this podcast and all other Children's Mercy podcasts.