Omar Abdel-Wahab, MD, already had a demanding career caring for patients and fulfilling all of the ancillary requirements that modern healthcare dictates when he started as a fellow at Memorial Sloan Kettering Cancer Center (MSKCC) in 2007.
As a resident and fellow, he was thunderstruck by the lack of effective therapies available to his patients with leukemia. So rather than remain in a career path purely focused on clinical medicine, he began to immerse himself in basic and translational research.
Now an Assistant Member of the Human Oncology and Pathogenesis Program and the Leukemia Service in the Department of Medicine at MSKCC, Abdel-Wahab explores his long-standing interest in blood cancers. “I felt that the best way to advance better therapies was to go to a basic level and perform research myself,” he said with a tone of sheer humility. He knew of no other way to carve sorely needed inroads into the therapy-barren landscape of this oncologic subspecialty.
From Clinician to Researcher
“I was always interested in hematology and one of its areas most in need of advancing outcome—leukemia. Within the hematologic malignancies, acute myeloid leukemia and high-risk forms of myelodysplastic syndromes (MDS) are in great need for clinical improvement,” he explained. “And even though I was primarily interested in clinical work, it became clear to me that we had no really good, well-established therapies for those disorders.”
At that point, he decided to become a catalyst for change. Making the transition from patient-facing clinician to lab-bound clinician/researcher took personal and professional flexibility as well as tenacity. “It was definitely a huge change,” Abdel-Wahab admitted. “Most physicians who work in laboratory-based research already have a strong lab research background. But I really didn't have much. I only got into research about 10 years ago, during my fellowship period. But I went deeper, deeper, and deeper into the research, and then I just never left.”
Now while he continues to maintain a clinical-patient interface with two 3-week blocks of service to leukemia inpatients at MSKCC, about 80 percent of his time is spent in the lab and predicated on his goal of utilizing knowledge about genetic alterations in blood cancers to develop therapies to target those cancers.
Asked what his “typical day” looks like, Abdel-Wahab said it is probably not what one would envision for an MD. “My lifestyle and day is very different from that which other clinicians experience,” he offered. While his team handles work at the bench that would seem to be the very pulse of the research, Abdel-Wahab takes more of directorial role, in addition to the aforementioned 6 weeks of clinical work. And then there is the gargantuan task of funding the lab and its potentially life-saving efforts. “I have to write for grants constantly,” he explained. “And in academia, there is a lot of travel which I didn't initially realize. I travel at least twice a month—sometimes weekly—to conferences or meetings or to give seminars.”
But any effort, however rigorous, would be worth the opportunity to hone in on a true “precision medicine” approach for so many patients in need of help. “We have a chance to develop therapies that will act on the molecular alterations specific to a person's own tumor. That is precision medicine, and that is something we take very seriously,” said Abdel-Wahab.
“My primary interest is in identifying those genetic alterations that cause leukemias,” he explained of his work, “then utilizing that knowledge to develop new therapies. We are trying to understand genetic mutations that are present in existing cancers, those that occur during the lifetime of an individual within the tumor itself. Many of these alterations are associated with age—the older you are the more likely you are to have them. While we understand a great deal about these mutations already, what is not well understood is how some of these mutations actually drive the disease. And exactly how to develop therapies to target these alterations is not worked out at all in many cases,” he lamented.
But important headway is being made, thanks in part to work within his lab. He began a brief description by first noting that, in healthy cells, RNA must be processed in a particular way to allow translation of proteins that enables molecules to do the actual work in the cells.
“But it's been found quite recently that the process of making RNA into a functional protein product can go awry in cancer; it is very common in leukemia and MDS,” he said. “In fact, there are specific mutations in four RNA splicing factors that are very frequent in leukemia. We know that about 50 percent of the patients with MDS have alterations in RNA splicing factors.”
The researchers have since observed that those four RNA splicing factor mutations occur in an exclusive manner, never simultaneously. “We figured out the reason for that: if they co-exist they are lethal to one another. This further allowed us to identify that cells that carry splicing factor mutations that promote cancer are very sensitive to any further perturbations to the RNA splicing process. Therefore, drugs that modulate RNA splicing preferentially kill cells that contain splicing factor mutations.”
The oncologist and his team are now working with partners in the industry in hopes of developing drug therapies to overcome splicing errors caused by mutations in a variety of RNA splicing factors, including the splicing factor 3b, subunit 1 (SF3B1) gene. The effort was recently described in literature: “The presence of mutations in SF3B1 leads to an error known as aberrant splicing, which, although still poorly understood, seems to promote disease by altering the production of number of proteins that are crucial for cell survival and differentiation. An investigational drug called H3B-8800 works to target cancer cells within mutations in SF3B1 to then trigger apoptosis” (Nat Med 2016;22(9):967-9).
Abdel-Wahab is understandably eager to point out that a phase I clinical trial based on this concept is now under way. “The trial utilizes information that modulates RNA splicing for patients with refractory myeloid leukemias bearing a splicing factor mutation. This trial is a critical step; the goals are to figure out the proper dose and to assess safety and tolerability.”
His lab, known for its strident work in genetically engineered mouse models, routinely also puts human cells into mice in order to draw important and unique observations. But this trial crosses the bridge from animal models to human beings. “This trial is a first in-human study pertaining to this particular area of our work, so we are very excited about it,” said the oncologist. “Getting to the human phase will be so interesting to all of us who have worked so hard to get this far.”
In the meantime, work with mouse models chugs on, because the lab team is working on a multitude of other therapeutic approaches as well.
As Abdel-Wahab awaits the completion and results of the clinical trial, he clearly hopes the entirety of health care gets on board with more proactivity in collecting data for future research and reference.
“One of the challenges I've noticed is that, even though we have a lot of knowledge about molecular alterations present in leukemia, and even though we can test for these things in clinical practice, it is not often done. Why? Because we do not have a therapy today that would target that mutation,” Abdel-Wahab explained. “Oftentimes genetic testing is not performed in a clinical setting because knowledge of these mutations may not make a difference to the patient today. But what we don't know is what is going to be available tomorrow.
“Even here at our own center we are only now starting to test for all mutations in these RNA splicing factors in a clinical setting. So even I cannot tell you how many patients in need of therapy could be eligible for this study today. I think we need to adopt more of a forward-thinking approach to collect this information prospectively with the hope that it might make difference to a patient in the future,” he stressed. “We can't stop with today.”
Valerie Laberta is a contributing writer.
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