An Oncogenic Route to Targeted Therapy for Bladder Cancer

Bladder Cancer: Bladder CancerRaie T. Bekele, PhD, has traveled the globe in pursuit of his career as a bladder cancer biologist with a research interest in DNA repair processes and MAPK signaling pathways. Originally from Addis Ababa, Ethiopia, Bekele said several childhood experiences inspired him to pursue a life in science. “My parents knew the value of education, so they impressed that on me. My dad was a soil scientist. He studied in Russia and Germany, and then he moved back to Ethiopia and worked in the Agricultural Research Organization. That's where I gained some inspiration to pursue science.”Raie T. Bekele, PhD: Raie T. Bekele, PhDIn his native Ethiopia, Bekele spoke Amharic, an ancient language some 3,000 years old, but transitioned linguistically as he started moving to different parts of the world. “I moved abroad and received my BSc in biochemistry and cell biology from Jacobs University in Bremen, Germany, “he told Oncology Times, noting that classes there were instructed in English. “That was followed by a PhD in biochemistry from the University of Alberta in Canada. I then moved to the U.S. for postdoctoral training, first at Massachusetts General Hospital and then at Dana-Farber Cancer Institute. Currently, I am an instructor in Radiation Oncology at Dana-Farber Cancer Institute and Harvard Medical School.” Bekele pointed to a few other “inspirations” that “...were woven together in a motivation factor for me. I can remember when, at a very young age, I first heard about death. I tried to make sense of it when a close family member died of cancer. I was very inquisitive and I wanted to understand what death actually was. That stuck with me for a while. “The next inspiration that I remember was the movie ‘Jurassic Park.’ When I watched that movie and saw amazing giant creatures supposedly cloned from a piece of sequence of DNA, I was fascinated. It seemed very exciting. Back home in Ethiopia, people did not talk about dinosaurs and things like that. So it captured my young imagination. For a long time, I wanted to have my own dinosaur park,” said Bekele, punctuated with laughter. “I watched that movie at least four or five times and heard the characters talk about recombinant DNA technology. I didn't understand what it was, but I wanted to.” The final thread in Bekele's inspiration tapestry came during the height of the 1990s HIV epidemic in Africa. “A lot of people were dying and there was no cure. On the radio and TV, they were always saying, ‘HIV is here, be careful,’ and do this, do that. It made me want to go into the biomedical field to search for cures and understand the biology of diseases.” Making It Happen Now a cancer biologist, Bekele said it was during his doctoral research in Canada that he dove into studying lipid signaling pathways. “Because of my interest in cancer, I spent a lot of my time studying signaling pathways that are activated in breast cancer. Then, when I moved to the U.S., I went initially to Massachusetts General Hospital to work on ovarian cancer research for a year. Then I finally transitioned to Dana-Farber, where I am right now, working on bladder cancer research. So, as you can see, I'm cancer agnostic since my interests are not on a particular type of cancer, but on understanding signaling pathways or alterations within cancer that help them to grow. Once we know those alterations, we can target them.” Bekele is now working in the laboratory of Kent Mouw, MD, PhD. “I am looking for signaling pathways that are activated in bladder cancer in a cohort of patients who have alterations–copy number amplification of a RAF1 gene that particularly drives that cancer,” Bekele explained. “Current standard of treatment is combination chemotherapy, given to most patients. But now we hope to find a more personalized treatment based on the genomics of the individual patient and the tumor of the patient. So now when a patient comes in, their tumor is sequenced and we check to see the particular alterations. My research focuses on identifying common alterations and then targeting them. I was able to identify a group of patients who have a particular alteration in their genomic DNA, which drives their tumors. This alteration is called copy number amplification of the RAF1 gene.” He meticulously explained that, in a normal bladder, there may be two copies of a given gene. “However, when it becomes a tumor, there may be 10 copies of that particular gene or even 50 copies. So now we grow the tumor in mice; we test them with novel inhibitors and see if those drivers are actually driving the tumor. I use a functional genomics approach and ask, ‘Is their copy number amplified? Yes. Is that copy number actually driving the tumors or is it just an artifact?’ “We found out that those amplifications are actually drivers. These genes are growth signaling pathways that push the cancer to grow, causing the normal bladder to become tumorigenic,” he revealed. “This was unknown before. We didn't know why nearly 20 percent of patients with invasive bladder cancer have those amplifications. So, we used cell biological techniques to knock out that gene, silence it from being expressed, and see if the tumor grows or not. We published this finding in the Journal of Clinical Investigation (2021; https://doi.org/10.1172/JCI147849).” Based on the findings, Dana-Farber is recruiting patients with RAF1 amplifications to treat them with novel inhibitors that will potentially target those alterations. This therapy is called MAPK inhibitor therapy. “There are companies that have drugs that can target those pathways, but previously they would not have been interested in treating those bladder cancer patients because they did not know that those amplifications existed or if they would drive the tumor growth,” Bekele explained. “So, in this way, we may be able to provide personalized treatment that was not available to this patient population before.” Bladder Cancer Specifics Bekele explained there are two types of bladder cancer: one is non-muscle-invasive and the other is muscle-invasive. “The muscle-invasive bladder cancer is very aggressive, and patients do die from it,” he said. “The standard of care is cisplatin-based chemotherapy. However, most of the patients relapse from that treatment. After they relapse, the prognosis isn't good. We found this amplification in those groups of patients who are not going to respond to those treatments.” Because there is some beneficial effect from chemotherapy, almost all patients receive it. “MAPK inhibitor therapy is a new, targeted therapy, so potentially it will be tested on patients who have relapsed from chemotherapy and immunotherapy treatments. There are a lot of steps involved in the clinical trial process to determine if this could result in a more durable treatment,” Bekele explained. Named a 2022 Young Investigator Award recipient by the Bladder Cancer Advocacy Network to further this investigation, Bekele stated, “I'm really hopeful this will be part of the arsenal that we have as scientists to treat patients with bladder cancer in the coming years. That's the goal. And we're expanding our research to determine if the signaling pathway has implications outside the cancer cells and modulates the environment of the cancer cells to prevent immune cells from being functional. If that's the case, we can expand the treatment not only to those amplified patients, but also to other bladder cancer patients who can benefit from the change in the tumor microenvironment.” Defining the big takeaway of this work, Bekele said, “RAF1 copy number amplification was an underappreciated signaling pathway in its role as a driver for bladder cancer. What I would want other oncologists to appreciate is the fact that RAF signaling pathway is relevant in bladder cancer. Most people think about this signaling pathway in terms of its twin protein, called BRAF. Whereas BRAF alters through mutation, here we have copy number alterations. What we have shown is that copy number amplification could, similarly to mutation, have an impact on driving tumors. And drugs targeted to copy number amplification could provide new ways of identifying biomarkers in this patient population.” Valerie Neff Newitt is a contributing writer.

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