image: Annabelle Anandappa, MD.
Credit: Photo/Andrew Higley/UC Marketing + Brand
Over the last few years, cancer researchers have placed significant focus on a group of genes called RAS as a target for new treatments that previously were considered “undruggable.”
In healthy human cells, RAS genes act as a light switch: When turned on, they signal the cell to divide — but when mutated in certain cancers, the switch stays in the “on” position, leading the cancer cells to divide and grow uncontrollably. Drugs that target RAS work by blocking this “on” signal, weakening the cancer cells’ ability to grow.
Most research of treatments targeting RAS has focused on solid tumors, including pancreatic cancer, but now a University of Cincinnati Cancer Center young investigator is testing whether RAS inhibitors can be effective as a treatment in blood cancers.
Annabelle Anandappa, MD, has received the ASCO Conquer Cancer Women Leaders in Oncology Endowed Young Investigator Award and a Damon Runyon Physician-Scientist Training Award to support preclinical research on the use of RAS inhibitors to treat acute myeloid leukemia (AML).
Targeting RAS in blood cancer
Anandappa explained that RAS mutations are found in about 15% to 20% of all AML cases at diagnosis, and new data suggests these mutations are associated with the development of treatment resistance for newly approved targeted AML therapies.
“We think this is a particularly timely project because we’ve known for a long time that RAS mutations are present in AML, but it wasn’t always clear how significant they were in terms of driving outcomes,” said Anandappa, a Cancer Center physician researcher and clinical instructor in UC’s College of Medicine. “Patients that relapse after initial targeted therapies don’t have great treatment options, so I think that’s one of the main things that’s motivating the study of RAS in this context.”
The one-year, $50,000 ASCO Young Investigator Award will support Anandappa’s continued efforts to study how a certain drug in a class called RAS(ON) inhibitors affects AML.
“Our initial studies have shown that these drugs are effective at inhibiting the growth of leukemic cell lines,” she said. “So the next steps this award will allow is to begin studying these RAS(ON) inhibitors in patient samples and animal models and see what impact these kinds of drugs have directly on the disease.”
Combination therapy potential
The four-year, $460,000 Damon Runyon grant is designed to bridge the gap that can appear after physician researchers complete their fellowships and before they receive funding as independent researchers.
“That’s a really important funding mechanism, and I’m really grateful Damon Runyon provides this funding, because this can be one of the more tenuous times in a researcher’s career trajectory,” Anandappa said. “I’m really grateful to know I can have the protected time to dedicate to being in the lab.”
The Damon Runyon funding will allow Anandappa to study a second RAS(ON) inhibitor’s effects on AML. Additionally, she will research how RAS interacts with genes associated with inflammation in AML.
“This subset of AML that has RAS mutations seems to be associated with increased inflammation,” she said. “What I'm hoping to build upon from that first year of work is ideally to see how inflammation may cooperate with RAS to drive AML and to see if targeting inflammation together with RAS would potentially have an even greater impact in treating AML.”
To look for a possible target, Anandappa will use CRISPR technology to screen through a panel of genes known to play a role in inflammation.
“The way the screen works is you’re targeting one by one each of those gene targets that are implicated in inflammation and looking to see if targeting those increases the ability of the drug to kill the cell,” Anandappa said. “Then that would tell us that targeting that gene plus the drug targeting RAS would be a potential synergistic approach to treatment.”
Anandappa said RAS mutations and treatments are a growing area of expertise for the Cancer Center, and she is excited to continue to build on this knowledge.
“I feel like it’s an opportunity to have more collaboration across blood cancers and solid cancers and learn more from each other in that respect,” she said.
Supportive mentorship
Linde Miles, PhD, and Daniel Starcyznowski, PhD, will serve as mentors on the projects. The research will combine the Starcyznowski lab’s expertise in inflammatory signaling in myeloid malignancies with the Miles lab’s focus on AML mutations, including RAS.
“I can’t say enough good things about Dr. Starczynowski and Dr. Miles and the way they complement each other in terms of their mentorship styles and expertise,” Anandappa said. “I think the project wouldn’t be possible without both of them and the insights they’re bringing — and also just personally and professionally, they have been incredible mentors to me.”
Miles noted the two grants are highly competitive and selected by a committee of established leaders in the fields of hematology and oncology, highlighting Anandappa’s potential as an independent physician researcher.
“Being given these awards underscores the promise that leaders in the field see in the awardees to become future independent physician scientists, but also future leaders in the field, given their current trajectories,” said Miles, Cancer Center member, member of Cincinnati Children’s Division of Experimental Hematology and Cancer Biology, and assistant professor of Pediatrics in UC’s College of Medicine. “It has been great to watch Annabelle further develop her confidence with new techniques and concepts as well as take true ownership of her project and drive it independently.”
From lab bench to bedside
Anandappa said she was always drawn to science and studied biomedical engineering as an undergraduate with the goal of eventually running her own research lab.
“Through working in a lab, I interacted with physician scientists, and that was my first gateway of thinking about how you could have potentially more impact by not only studying something in the lab but then also being able to have a foot in the clinic and bridging the gap between the two,” she said.
As she begins her role as a clinical instructor, Anandappa will also work eight weeks out of the year as a physician at the Blood Cancer Healing Center’s inpatient unit. She said working both in the lab and with patients provides inspiration for all of the work she does.
“I find incredible fulfillment in spending time with people in the inpatient setting, and it drives me and motivates me to do more in the lab and try to ideally get to these translational endpoints we hope will eventually lead to better therapies for our patients,” she said.
Miles said Anandappa’s perspective as both a researcher and a clinician has made an impact in the lab.
“Having Annabelle as a member of the lab has added a crucial viewpoint for looking at projects and questions and reminding our lab to focus on the clinical implications of what we do,” said Miles. “That perspective has on many occasions altered the way my graduate students think about their projects and their focus within those projects.”
Other collaborators on the research include Andrew Waters, Ken Greis and Shesh Rai.