SC CTSI KL2 Scholar awarded NINDS K08 grant to examine the role of a new gene type in glioblastoma treatment

September 01, 2021

We sat down (virtually!) with Dr. Frank Attenello, a recipient of the SC CTSI Mentored Career Development in Clinical and Translational Science award. We hear about his new K08 grant from the National Institute of Neurological Disorders and Stroke within the National Institutes of Health, and what he hopes to learn. Congratulations to Dr. Attenello on this great accomplishment!

1. In layperson’s terms, tell us a little about your grant and the work you have proposed.

Glioblastoma (GBM), the most common primary brain tumor, has a 15-month patient survival due to the inevitable recurrence of tumor despite comprehensive treatment, including chemotherapy, radiation therapy and surgery. Our study focuses on a new type of gene – long noncoding RNAs (lncRNAs) – that comprise 80% of the genome. Because few GBM lncRNAs have been studied, characterizing new candidates among this abundant and novel class of genes may significantly improve chemotherapy efficacy.

We noticed a particular lncRNA, linc02454, was highly increased following chemotherapy in GBM. This gene showed promise, as high expression of this lncRNA is associated with worse patient outcomes, while knockdown of this lncRNA decreases tumor growth. We further noted that the expression of this novel lncRNA was highly associated with a central gene in GBM biology (and target of multiple clinical trials), CXCR4. We hypothesize chemotherapy treatment increases linc02454 tumor expression and that this linc02454 subsequently produces GBM resistance to chemotherapy (by increasing CXCR4). Our study will evaluate the exact manner by which chemotherapy regulates lncRNAs, and subsequently how these lncRNAs affect GBM sensitivity to chemotherapy. 

The grant is a K08, a clinician-scientist research career development award. It provides both laboratory funding and protected research time to improve my training in bioinformatics, transcriptional regulation and GBM treatment resistance. It includes a mentorship team to guide my training and research progress.  My primary mentor is Dr. Yali Dou, a professor in Medicine, Biochemistry, and Molecular Medicine, and international expert in chromatin gene regulation in cancer. Dr. William Mack, a successful USC neurosurgeon-scientist and head of the USC R25 resident research training program, serves as a co-mentor. Dr. Behnam Badie, a national glioblastoma expert who is faculty and chair at City of Hope, also serves as a co-mentor.

2. What got you interested in this topic initially?

Working with glioblastoma patients is challenging. Regardless of how well a surgeon performs surgery, and regardless of whether all the tumor is removed, the tumor inevitably grows back. Not only do these tumors return, but they often show that they are more aggressive after chemotherapy. Improving chemotherapy efficacy appears to be a promising avenue for improving patient outcomes.

I developed interest in potential tumor treatment targets during my post doctorate fellowship, when our group published the first large-scale demonstration of functionality in many GBM long noncoding RNAs (lncRNAs). These lncRNAs were a new class of genes, representing a large, unstudied portion of the genome. I felt these lncRNAs may offer a great opportunity for study and eventual treatment.

As an added benefit, I also study traumatic brain injury, and the lncRNA we are studying in the K08 also affects neural stem cell behavior during injury.

3. What do you hope to learn as part of this grant?

Gene expression is highly altered in glioblastoma and other cancers, particularly in response to chemotherapy. During this grant, I hope to develop the scientific background and skills necessary to effectively study what drives these gene expression changes. Developing treatments to prevent or reverse these changes may lead to improved patient outcomes. 

4. What things have been challenging when it comes to conducting your research?

The field of transcriptional regulation and lncRNAs is a small one and finding expertise when facing challenges in our work has been difficult. I am especially appreciative of my K08 mentorship team, as they have provided guidance in the face of these challenges. In addition, while it is often challenging to assemble a productive, skilled, and motivated team in the lab, I’ve been fortunate to have found it in our group of staff and students. 

5. What have been rewarding aspects to conducting your research?

Working with a great team is incredibly rewarding. While we all work through shared challenges in the lab, we also share each other’s’ successes, whether it be running a successful experiment, publishing a new manuscript, or watching excited graduates move to the next phase of training. Furthermore, as a neurosurgeon, it is rewarding when discussing research with patients and families. They often express hope in the potential that ongoing work in our lab and throughout the world may improve outcomes. 

6. What does this grant award mean to you and your career?

The grant is a fantastic opportunity for me to work with a very strong group of mentors and collaborators to develop an in depth understanding and skillset in transcriptional regulation and chemotherapy resistance. These skills will hopefully provide a strong foundation for a career grounded in (and bridging) both translational research and clinical care. 

7. How has the MCD KL2 program contributed to your success?

The KL2 program was a great help, providing early research support and protected time, while connecting me with mentors critical to my success. It was there that I learned skills for building and maintaining a laboratory, as well as grant writing. My mentors and the KL2 program staff further assisted me in writing two successful grant applications that funded our lab. I still regularly seek the guidance of my mentors from the KL2 program: Drs. William Mack, Berislav Zlokovic, and Thomas Chen. To this day, I also still regularly receive critical guidance from the KL2 program leaders, Drs. Steven Siegel and Cecilia Patino-Sutton.

8. Do you have a mentor? If so, how has this person helped you?

From a career standpoint, Dr. William Mack, a former KL2 awardee and neurosurgeon-scientist, has been a fantastic mentor for many years. He guided my progress as I assembled my lab, applied for grants, published data, and integrated academic pursuits into my clinical practice. I consider myself lucky that a successful surgeon-scientist is so heavily invested in my development and success.

My K08 primary mentor, Dr. Yali Dou – an international expert in chromatin and transcriptional regulation in cancer – has also been extremely gracious, guiding my scientific progress, and showing significant investment in my data, manuscripts, and grant applications.

NIH Funding Acknowledgment: Important - All publications resulting from the utilization of SC CTSI resources are required to credit the SC CTSI grant by including the NIH funding acknowledgment and must comply with the NIH Public Access Policy.