MD Anderson Research Highlights for January 26, 2022

HOUSTON ― The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recently published studies in basic, translational and clinical cancer research from MD Anderson experts. Current clinical advances include combination therapies for thyroid cancer and multiple myeloma, as well as discoveries to improve CRISPR/Cas9 gene editing, to identify biomarkers for immunotherapy response, to utilize T cell therapy for osteosarcoma and to understand of the role of LIP-1 in regulating ERK signaling.

New combination therapy offers promising treatment for BRAFV600E-mutant ATC

Anaplastic thyroid cancer (ATC) is a rare but aggressive form of the disease, with a median survival of five months and a one-year survival rate of 20%. Therefore, more effective treatments with long-term benefits are needed. In an updated analysis of the Phase II Rare Oncology Agnostic Research (ROAR) basket trial, led by Vivek Subbiah, M.D., and Maria Cabanillas, M.D., researchers assessed the safety and efficacy of dabrafenib plus trametinib in patients with BRAFV600E-mutated ATC and other rare cancers. In this updated analysis, the combination therapy — the first drugs to be approved by the Food and Drug Administration for the treatment of ATC — confirmed the substantial clinical benefit and manageable toxicity, achieving an overall response rate of 56%, including three complete responses. The one-year progression-free survival and overall survival rates were 43.2% and 51.7%, respectively. These findings confirm that dabrafenib plus trametinib provides a meaningful treatment option with long-term survival rates for patients with this rare, aggressive cancer. Learn more in Annals of Oncology.

Researchers develop model to predict CRISPR/Cas9 off-target editing and to improve allele-specific editing

The CRISPR/Cas9 technology allows scientists to edit target genes quickly and easily, which offers broad research and therapeutic applications. A guide RNA matching the target gene allows for specific editing, but off-target effects can occur when guide RNAs are similar to other genes, leading to unintended consequences. Further, the off-target effect limits the ability to edit specific gene alleles — when a disease-causing mutant allele may differ from the normal allele by just one base pair. A research team led by Rongjie Fu, Ph.D., Wei He, Ph.D., and Han Xu, Ph.D., developed a high-throughput system and computational methods to explore the sequence rules governing mismatch tolerance of guide RNAs. With their findings, the team designed a model-based prediction tool that can be used to minimize off-target gene editing. The rules inferred from the study also led to the development of a new strategy to improve the selectivity of allele-specific editing using mismatched guide RNAs. Learn more in Nature Communications.

Network analysis identifies potential new biomarkers and therapeutic combos for anti-PD-1 immunotherapy

Despite the success of immunotherapy, only a subset of patients can benefit from these treatments. To discover predictive biomarkers, a research team led by Chia-Chin Wu, Ph.D, and Y. Alan Wang, Ph.D., developed a network approach for identifying genes and pathways associated with responses to anti-PD-1 immunotherapy. The team’s prediction successfully identifies genes and pathways known to be associated with anti-PD-1, validating the approach. Integration of the top predicted genes and cancer genomic data identified hundreds of genes whose expression or alterations could affect anti-PD-1 response for each cancer type, and comparisons of these genes across cancer types suggests the immunoregulations associated with anti-PD-1 are tissue-specific. Some top genes led to a signature score that showed a good correlation with responses in six cohorts of melanoma patients. Further, looking at the top genes in context of drug targets identified targeted therapies that could potentially enhance response to anti-PD-1 therapies. Learn more in Nature Communications.

Genetically modified cell infusion blocks osteosarcoma tumor progression

Modified T-cell transfer therapy, designed to help a person’s own immune cells better target and attack cancer, has become a popular method for treating hematologic malignancies. However, research shows limited activity against large and heterogeneous solid tumors, such as osteosarcoma, with potential toxicity. Jiemiao Hu, Ph.D., and colleagues in the lab of Shulin Li, Ph.D., discovered that IL-12 (attIL12)-T cell infusions dramatically inhibited osteosarcoma and melanoma tumor progression in patient-derived and laboratory models, resulting in significantly prolonged survival time. The method of attIL12-T cell infusion, which targets tumor cells expressing the cell surface protein vimentin, also boosted the anti-tumor impact of known chimeric antigen receptor (CAR) T cells and T cell receptor (TCR) T cell therapies.  Results from the study also showed that attIL12-T cell infusion could potentially be used for a variety of types of large and heterogeneous solid tumors beyond what the study covered. Learn more in the Journal for ImmunoTherapy of Cancer.

Combination maintenance therapy safe and effective for multiple myeloma patients after stem cell transplant

The standard of care for newly-diagnosed multiple myeloma is induction chemotherapy, an autologous stem cell transplant (ASCT) and maintenance therapy with lenalidomide. However, this approach is typically not curative. Researchers led by Krina Patel, M.D., explored the safety and efficacy of a combination regimen of lenalidomide and ixazomib as oral maintenance therapy following ASCT. They sought to determine whether the regimen would improve clinical response in newly diagnosed multiple myeloma patients after ASCT without significantly increasing toxicity. Out of the 64 patients in the single-arm study, response rates deepened for 39 patients. The complete response rate was 43%, and the median progression-free survival was 73 months. Side effects included neutropenia, leukopenia, lung infections and diarrhea. Due to toxicity, doses of ixazomib and lenalidomide had to be reduced for 20 and 31 patients, respectively. Overall, the combination therapy was safe, had manageable side effects and produced greater than expected progression-free survival for newly diagnosed multiple myeloma compared with previous data reported in trials with maintenance with lenalidomide alone. Learn more in Clinical Cancer Research.

Study reevaluates role of LIP-1 in regulating ERK signaling during reproductive development

Extracellular signal-related kinases (ERKs) are signaling proteins critical for development and tissue homeostasis. In response to stimuli, ERK proteins are activated by the addition of a phosphorylation mark. They are later inactivated by dual specificity phosphatases (DUSPs) that remove the phosphorylation. This activity cycle is tightly controlled during many cellular processes and conserved across species. The laboratory of Swathi Arur, Ph.D., uses the C. elegans model system to understand regulation of ERK signaling during ovary development. A new study led by Debabrata Das, Ph.D., found that LIP-1 — a DUSP homolog previously thought to regulate ERK activity in the C. elegans ovary — does not, in fact, work to inactivate ERK in this tissue. The results demonstrate that each DUSP protein may have distinct functions in different tissues. As DUSPs also regulate ERK during cancer progression, the study highlights the need for caution when interpreting and generalizing the role of DUSPs in regulating ERK activity. Learn more in the Proceedings of the National Academy of Sciences. 

In case you missed it

Read below to catch up on recent MD Anderson press releases across the spectrum of cancer research.

• MD Anderson and Yingli Pharma initiate strategic collaboration to advance development of multiple oncology programs
• Nano-sized vesicles with ACE2 receptor could prevent, treat infection from current and future strains of SARS-CoV-2
• MD Anderson and Eisbach Bio announce strategic collaboration to develop medicines targeting epigenetic machinery in oncology

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