Meeting News Coverage

Top Takeaways from ASH: Splicing alterations could hold key to prognosis, therapeutic targets

The use of splicing modulations in the treatment of hematologic malignancies was lauded by experts as among the most exciting advances highlighted at the annual American Society of Hematology Annual Meeting and Exposition in Orlando, Fla.

“The bottom line is that this is a disease in which we can alter splicing by using very specific modulators,” Catriona Jamieson, MD, PhD, associate professor of medicine, division of hematology-oncology, co-leader of the hematologic malignancies program, and director of stem cell research at UC San Diego Moores Cancer Center, told Healio.com.

   Catriona
  Jamieson

“This is very good because we are now considering the patient from a precision therapy standpoint in a holistic and comprehensive way.”

Splicing alterations offer new direction 

Attendees witnessed a distinct and “actionable” shift toward the concept that splicing alterations drive changes in the biology of various hematologic malignancies, Jamieson said.

“Before, we were all trying to go after DNA mutations — and there are so many DNA mutations, so what do you do?” she said. “For the first time, we started to see you could look for splicing alterations as predictors of a poor prognosis or look at them as potential therapeutic targets.”

Mark Levis MD, PhD, professor of pharmacology and molecular sciences, Johns Hopkins University School of Medicine, Baltimore, provided a cellular-level picture. 

Mark Levis

“There is a small collection of proteins in a cell whose job it is to splice up the messages from genes as a normal biologic function,” he told Healio.com.

Although the field has known about mutations in this spliceosome assembly in hematologic malignancies for a few years now, Levis said the mechanisms and potential targets have never been fully understood.

Jamieson described how cancers can become de-regulated and learn resistance to therapies in the spliceosome.
“They make different isoforms of the same gene, so that can be made into a slightly different-looking protein,” she said. “That in and of itself is targetable.”

She noted that conducting studies involving splicing modulation is different than investigations targeting a single rare mutation and emphasized the implications in hematology.

“We’ll be targeting more common changes that affect a number of cancers,” she said. “We can start clinical trials earlier in blood cancers because we can sample blood and bone marrow to look at the effects very quickly, as opposed to having to re-biopsy a solid tumor, which is much more difficult and fraught with potential complications.”

Promising data, looking ahead 

New findings on splicing modulation in myelodysplastic syndrome and acute myeloid leukemia by an international team of researchers at Memorial Sloan Kettering Cancer Center in New York, Fred Hutchinson Cancer Research Center in Seattle, and Gustave Roussy Cancer Center in France were revealed during the plenary session.

“For the first time, they presented how these mutations work, and it makes any cell with this mutation vulnerable to a spliceosome inhibitor,” Levis said. “You’re going to see a new arms race now in the pharmaceutical industry to develop spliceosome inhibitors.”

However, Levis expressed equal parts skepticism and frustration — about the therapy becoming available for use in practice anytime soon and about the pace of FDA approvals.

“While we’re all very excited that we found out the biology and have a target, we’re going to groan again that we have a another subtype of patients, we’ve got to put only them on trial, how are we going to get a drug like this approved?” he said.

Similar promising results from an investigation at UC San Diego, La Jolla, Calif., using a splicing modulatory agent in secondary AML were presented. The data showed not only normalized splice isoform expression patterns but reduced leukemia stem cell survival, suggesting potential for diagnostic biomarkers and use in therapy-resistant disease.

Jamieson pointed to other compelling results from researchers at Harvard Medical School, Boston, and Washington University School of Medicine, St. Louis, that showed “a very specific splicing modulator seemed to be very effective in U2AF1-mutated high-risk MDS and AML.”

Additionally, she highlighted “provocative” data by investigators at the Mitchell Cancer Institute, University of South Alabama, demonstrating how the mixed lineage leukemia complex could not be broken down with splicing of the nuclear protein SON, abundant in hematopoietic cells and organs as well as embryonic stem cells.

“Alternatively-spliced isoforms of SON seemed to prevent degradation of the MLL complex so that basically the leukemias became more resistant,” she said.

Jamieson called the splicing modulation theme that prevailed through the meeting “very optimistic,” but said that it will take at least another 1 or 2 years before such therapies come to the fore clinically. by Allegra Tiver

References:

Crews LA, et al. Abstract 567. RNA Splicing Modulation Impairs Acute Myeloid Leukemia Stem Cell Maintenance.

Kim JH, et al. Abstract 2426. Son and Its Alternatively Spliced Isoforms Control MLL Complex-Mediated H3K4me3 and Transcription of Leukemia-Associated Genes.

Lee S CW, et al. Abstract 4. Therapeutic Targeting of Spliceosomal Mutant Myeloid Leukemias through Modulation of Splicing Catalysis.
Shirai CL, et al. Abstract 1653. Preclinical Activity of Splicing Modulators in U2AF1 Mutant MDS/AML.

Disclosure:

Levis reports no relevant financial disclosures. Jamieson reports that her lab receives unrestricted research funding from CTI Biopharma and Johnson & Johnson.

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