MD Anderson Research Highlights for July 27, 2022

Featuring targeted therapies for BPDCN and AML, insights to improve immunotherapy in pancreatic cancer, and surgical advances for metastatic cancers

The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recent basic, translational and clinical cancer research from MD Anderson experts. Clinical advances include treating hematologic cancers with effective targeted therapies, circulating tumor DNA as a biomarker for recurrence with colorectal liver metastases, and using magnetic resonance imaging (MRI) to guide surgical decisions for patients with lateral pelvic lymph node metastases in rectal cancer. Laboratory findings offer new understanding of the pancreatic cancer immune microenvironment, melanoma cell states, TP53 mutation status in acute myeloid leukemia (AML), and potential targets for metastatic prostate cancer and GNAS­­-mutant colorectal cancer.

Tagraxofusp shows long-term benefit for patients with BPDCN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare but highly aggressive hematologic malignancy. Naveen Pemmaraju, M.D., led the practice-changing Phase I/II clinical trial that showed high response rates in newly-diagnosed BPDCN patients treated with tagraxofusp, an anti-CD123 targeted therapy. Those results led to tagraxofusp becoming the first and only approved targeted therapy for treatment of patients with BPDCN. A new long-term analysis, with a median follow-up of almost three years, showed a complete response or clinical response in 57% of patients and an overall response rate of 75%, with a rapid time to onset. Additionally, relapsed or refractory (R/R) patients showed a 58% response rate, which is significant since there has been little benefit reported in this setting. These data confirm the efficacy of tagraxofusp as a therapy for first-line treated patients with BPDCN and as a possible option for patients with R/R disease. Read more in the Journal of Clinical Oncology.

Venetoclax plus gilteritinib associated with high response rates in FLT3-mutated AML
Relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) is typically resistant to venetoclax, and response durations can be short when treated with single agent FLT3 inhibitors, such as gilteritinib. A multicenter study led by Naval Daver, M.D., included 61 patients with R/R FLT3-mutant AML who were treated with a combination of venetoclax and gilteritinib, based on robust preclinical synergy for the combination. The composite complete response rate for FLT3-mutated patients was 75% (with a clinical response rate of 38%) and was similar among patients with or without prior FLT3 inhibitor treatment. FLT3 molecular response was achieved in 60% of evaluable responders. The most common grade 3/4 adverse events were cytopenias in 80% of patients, and almost half the patients had dose interruptions to lessen the myelosuppression commonly encountered with venetoclax combinations in R/R AML. The results suggest that venetoclax plus gilteritinib is a highly active and tolerable oral combination regimen that potentially improves response rates over existing therapies in a high-risk group of patients with FLT3-mutant R/R AML. Read more in the Journal of Clinical Oncology.

Study offers insights into T cell states in pancreatic cancer immune microenvironment
Pancreatic cancer remains a challenging disease with few effective treatment options. With limited success from immunotherapy, there is a need to further understand the tumor immune microenvironment in order to develop effective therapeutic strategies. In a new study led by Aislyn Schalck, Donastas Sakellariou-Thompson, Ph.D., Nicholas Navin, Ph.D., and Chantale Bernatchez, Ph.D., researchers used single-cell RNA sequencing and T cell receptor analysis to profile 80,000 T cells from 57 pancreatic tumor samples, 22 matched normal samples and cultured tumor-infiltrating lymphocytes (TILs). The researchers identified 20 unique T cell states defined by different gene expression profiles and discovered that certain states, such as dysfunctional and inhibitory T cells, often were found together. Analysis of the cultured TILs showed the most frequently occurring clones were preferentially expanded. This study provides a better understanding of the immune microenvironment and a framework to advance TIL therapies in pancreatic cancer. Learn more in Cancer Discovery.

Protein expression could identify TP53 mutation status, improve risk prediction for AML
TP53 mutations are associated with adverse outcomes in acute myeloid leukemia (AML), highlighting the need to understand how these mutations and resulting mutant protein status can be used to guide therapy selection. However, there has not been a comprehensive study of the landscape of TP53 mutations, copy number changes and mutant protein expression in patients with AML. Therefore, researchers led by Mehrnoosh Tashakori, M.D., Ph.D., and Joseph D. Khoury, M.D., performed an integrated genomic and proteomic analysis to characterize informative elements for determining risk status across AML subgroups. They showed that TP53 mutation status and copy number changes vary across subsets of AML. They also demonstrated that p53 protein expression, detected by immunohistochemistry with quantitative digital image analysis, correlated well with TP53 mutation and copy number status. Their findings suggest that protein expression could be a simpler approach to identifying patients with corresponding TP53 mutations, offering opportunities to refine risk stratification for AML. Learn more in Blood.

Comprehensive profiling uncovers molecular programs driving melanoma cell states
Gene expression studies have identified distinct subclasses of melanoma cells, but the molecular pathways regulating these gene expression signatures and corresponding therapeutic outcomes are not well understood. A team of researchers led by Scott Woodman, M.D., Ph.D., performed comprehensive molecular profiling on 68 patient-derived melanoma cell lines, including analyses of genomic, transcriptomic, proteomic and non-coding RNA features. The researchers defined molecular programs underlying three distinct classes of cell types and demonstrated these programs are conserved between tumors and laboratory cell lines. They identified defining gene expression signatures that can be used to categorize both cell lines and tumors, and showed these cell types are associated with outcomes to immunotherapy and cellular therapy. These findings provide a new understanding of the underlying features of melanoma and provide an important resource for future research.  Learn more in Nature Communications.

Targeting brain NMDA receptors could block hypertension from calcineurin inhibitors
Calcineurin is a signaling protein critical for many physiological functions, including T cell activation and heart function. Calcineurin inhibitors, such as cyclosporine and tacrolimus, are used as immunosuppressants for organ transplants and as treatments for autoimmune disorders. Prolonged use of these drugs can cause high blood pressure (hypertension), but the underlying mechanisms are not well-understood. In a new study led by Jing-Jing Zhou, Ph.D., and Hui-Lin Pan, M.D., Ph.D., researchers demonstrated that calcineurin in the hypothalamus region of the brain is critical for restricting sympathetic nerve activity and regulating blood pressure. Using laboratory models, the researchers showed that tacrolimus diminished calcineurin activity in the brain, leading to activation of N-methyl-D-aspartate (NMDA) receptors, increased firing of sympathetic-related neurons and hypertension. Targeting NMDA receptors blocked the blood pressure increase caused by tacrolimus treatment, suggesting these receptors could be a new target to treat hypertension caused by calcineurin inhibitors. Learn more in Circulation Research.

Postoperative ctDNA associated with recurrence of colorectal liver metastases
For patients with colorectal cancer that spreads to the liver, surgery plus chemotherapy has a nearly 60% five-year survival rate, but better biomarkers are needed to identify patients at high risk of recurrence to guide treatment strategies and tailor surveillance. This study, led by Timothy Newhook, M.D., Michael Overman, M.D., and Jean-Nicolas Vauthey, M.D., analyzed the association between circulating tumor DNA (ctDNA) and outcomes following curative-intent liver resection for colorectal liver metastases. A total of 48 patients were included in the study, with ctDNA detected before and after surgery for 14 patients, before surgery only for 19 patients, and not detected at all for 11 patients. Median recurrence-free survival was six months in patients with ctDNA before and after surgery, was not reached for those with ctDNA before but not after surgery, and was 33 months for those with no ctDNA detected at all. These results indicate that perioperative ctDNA is strongly associated with risk of recurrence, more accurately predicts recurrence than preoperative ctDNA alone, and identifies patients who achieve ctDNA-clearance by curative-intent surgery. Learn more in Annals of Surgery.

MRI can effectively guide surgical decision-making for lateral pelvic lymph node metastases in rectal cancer
In Western countries, locally advanced rectal cancer is typically treated with total neoadjuvant therapy (TNT) and total mesorectal excision (TME). Lateral pelvic lymph node (LPLN) metastasis is an important clinical problem in rectal cancer, and there is no global consensus on how to treat it. This retrospective single-institution study, led by Oliver Peacock, B.M.B.S., Ph.D., and George Chang, M.D., examined outcomes when magnetic resonance imaging (MRI) was used to facilitate appropriate selection of patients requiring additional surgery, called lateral pelvic lymph node dissection (LPLND) following TNT. LPLND traditionally has been performed in Eastern countries but has not been widely adopted in the West due to concerns about potential morbidity and technical difficulty. This study identified 158 patients with enlarged pre-treatment LPLNs who received TNT; 88 patients (56.0%) underwent LPLND, after MRI assessment by a multidisciplinary team. The MD Anderson team reported good outcomes for LPLND with major morbidity (19.3% vs. 17.0%) and recurrence rates (3.4% vs. 4.6%) that did not differ between the patients who did and did not receive LPLND, indicating that MRI can be used to select patients for LPLND. Learn more in Annals of Surgery.

Retinoic acid receptor regulates bone formation from prostate cancer bone metastases
Prostate cancer that has metastasized to the bone is an aggressive disease without effective therapies. Bone metastases develop into bone-forming lesions that drive progression and treatment resistance, and strategies to target the bone-formation pathways are unavailable. In a new study led by Guoyu Yu, Ph.D., Paul Corn, M.D., Ph.D., and Sue-Hwa Lin, Ph.D., researchers demonstrated that activation of the retinoic acid receptor (RAR) inhibits the molecular program driving the transition from endothelial cells to osteoblasts, reducing bone formation from metastatic cells. Treating laboratory models with RAR agonists blocked endothelial-to-osteoblast transition and reduced tumor growth and tumor-induced bone formation. The researchers also clarified the mechanistic pathway underlying this process. These findings suggest that RAR agonists could be repurposed to block bone formation from prostate cancer bone metastases and improve patient outcomes. Learn more in Cancer Research.

Downstream GNAS mediators are potential therapeutic targets for GNAS-mutant tumors
Activating mutations in the GNAS gene — which encodes a signaling protein called Gαs — leads to the activation of pathways associated with cancer cell proliferation, but the mechanisms involved have remained unclear. Researchers led by Aditya More, Ichiaki Ito, Valsala Haridas and John Paul Shen, M.D., looked at peritoneal models of colorectal cancer with specific activating GNAS mutations in order to determine the tumors’ dependence on the GNAS pathway and to identify downstream targets. Using gene knockouts, they showed that these mutant tumors relied on GNAS to proliferate. The researchers were able to identify several downstream targets of GNAS signaling, including the PKA and Wnt pathways. Indeed, blocking PKA and Wnt signaling reduced the growth of GNAS mutant tumors, suggesting they could be potential therapeutic targets. These findings demonstrate oncogene addiction to GNAS mutations and offer potential new therapeutic strategies in patient with GNAS-mutant cancers. Learn more in Oncogene.

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