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Â鶹ӳ»­ MD Anderson Cancer Center¡¯s Research Highlights showcases the latest breakthroughs in cancer care, research and prevention. These advances are made possible through seamless collaboration between MD Anderson¡¯s world-leading clinicians and scientists, bringing discoveries from the lab to the clinic and back.

Recent developments include a combination therapy for acute lymphoblastic leukemia, new insights into the evolution of anaplastic thyroid cancer, a promising new treatment approach for?PTEN/p53-deficient prostate cancer, a novel pan-species artificial intelligence model to detect cancer cells, a neoadjuvant combination therapy to improve disease-free survival in kidney cancer, combination therapies to overcome treatment resistance in acute myeloid leukemia, and a bioinformatics tool for predicting immunotherapy treatment response.

Mini-Hyper-CVD regimen with inotuzumab and blinatumomab improves survival for patients with relapsed ALL
Adults with relapsed/refractory?acute lymphoblastic leukemia?(ALL) historically have experienced poor outcomes when treated with intensive?chemotherapy. Researchers led by??explored the addition of blinatumomab to low-intensity mini-Hyper-CVD chemotherapy with inotuzumab ozogamicin in a Phase II study. The study demonstrated the combination was safe and effective in patients with ALL. Among 110 patients, the combination resulted in a complete response rate of 83% and an absence of measurable residual disease in 82% of patients. Median overall survival (OS) was 17 months, and the three-year OS rate was 40% with a median follow-up of 48 months. The OS rate with mini-Hyper-CVD and inotuzumab alone was 34%, and the additional dose of blinatumomab improved the three-year OS rate to 54%. These long-term follow-up data confirmed the safety and efficacy of this regimen and suggest blinatumomab may further improve outcomes. Learn more in?.

New model improves understanding of anaplastic transformation in thyroid cancer
Patients with?anaplastic thyroid cancer?(ATC) ¡ª which often results from a transformation of pre-existing differentiated thyroid cancer ¡ª have a low survival rate, highlighting a significant unmet clinical need to better understand this rare, aggressive disease and to develop effective treatment options. Researchers led by?, and?, investigated this transformation using single-cell transcriptomes and genetic alteration data from patients with different thyroid cancer subtypes to create a model that tracks the evolution of ATC progression. They identified key milestones in the sequential programming of tumor cells and provided further insights into cell-cell signaling in the tumor microenvironment during ATC transformation. These discoveries can help the development of new therapeutic strategies to improve patient survival. Learn more in the?.

Combination therapy shows promise in preclinical models of?PTEN/p53-deficient prostate cancer
Patients with advanced castration-resistant?prostate cancer?do not respond well to androgen deprivation therapy or?immunotherapy, especially if they have mutations or defects in tumor suppressors?PTEN?and?p53. The immune checkpoint protein B7-H3 is overexpressed in advanced prostate cancer, but its role is poorly understood. Researchers led by Wei Shi, Ph.D., and?, identified B7-H3 as a novel immunotherapy target in?PTEN/TP53-deficient prostate cancer and uncovered its function in tumor progression and immunosuppression. Inhibiting B7-H3 using a monoclonal antibody in combination with?PD-L1 or CTLA-4 blockade?demonstrated significant tumor-suppressing activity in preclinical models, emphasizing this strategy as a viable option that merits further investigation in clinical studies. Learn more in?.

Novel pan-species AI atlas provides insights into the evolution of cancer development across species
Comparative oncology ¡ª the study of cancer across species ¡ª can provide insights into evolutionary mechanisms behind cancer development in humans and non-human animals, while also highlighting potential therapeutic strategies for human cancer treatments and animal conservation efforts. In a first-of-its-kind study, researchers led by?, used an artificial intelligence (AI) algorithm trained to recognize tumor cells, lymphocytes and stromal cells in human?lung cancer?samples taken from the Tracking Cancer Evolution Through Therapy (TRACERx) study. They applied this AI model to 120 tumor samples across 20 animal species, building a pan-species cancer digital pathology atlas that was highly accurate at classifying cancer cells, especially in canine transmissible venereal tumors (94% accurate) and Tasmanian devil facial tumor disease (88% accurate). This study highlights the potential of this pan-species AI model for identifying prognostic indicators of cancer in both animals and humans that could lead to further advances in the development of viable treatments in veterinary medicine and comparative oncology. Learn more in?.

Kidney cancer treated with neoadjuvant sitravatinib plus nivolumab shows immune responses
Complete or partial surgical removal of the kidney (nephrectomy) is the current curative standard of care for locally advanced?clear cell renal cell carcinoma?(ccRCC), yet 20-40% of patients will develop metastases after successful surgery.?Immune checkpoint therapy?and tyrosine kinase inhibitors, such as sitravatinib, given prior to surgery have the potential to improve outcomes in patients with ccRCC. Researchers led by?, and?, conducted a Phase II study to evaluate the efficacy and safety of pre-surgical, or neoadjuvant, sitravatinib plus nivolumab in patients undergoing nephrectomy for locally advanced ccRCC. While the objective response rate was only 11.8%, the 24-month disease-free survival probability was 88%. Blood and tissue analyses showed changes in the tumor microenvironment, resulting in an immunologically active tumor by the time of surgery. The study suggests future neoadjuvant trials should prioritize long-term survival endpoints such as disease-free survival. Learn more in?.

Combination therapy targets senescent cells to overcome chemotherapy resistance in AML
Acute myeloid leukemia?(AML) with overexpression of BCL-2 anti-apoptotic proteins is associated with aggressive disease progression and resistance to chemotherapy. While treatment with the BCL-2 inhibitor venetoclax plus chemotherapy results in high response rates, most patients eventually relapse, highlighting a need for more effective treatments. Recent findings have shown that chemoresistance is associated with cellular senescence, which occurs when cells stop dividing but avoid death, via upregulation of both BCL-XL?and BCL-2 activity. Researchers led by?, examined the use of PROTAC 753B, a dual BCL-XL/BCL-2 inhibitor, to effectively eliminate these senescent cells both?in vitro?and?in vivo. These results suggest the drug has potential as a viable therapeutic strategy to overcome chemotherapy resistance in AML. Learn more in?.

Novel triplet regimen delivers promising results in patients with?IDH1-mutated acute myeloid leukemia
The current frontline combination therapy for patients with high-risk?IDH1-mutated?acute myeloid leukemia?(AML) is effective, but relapses remain common for patients. In a first-of-its-kind study, researchers led by?, evaluated the safety and efficacy of ivosidenib and venetoclax as an oral doublet regimen and ivosidenib, venetoclax and azacytidine as a triplet combination. The overall composite remission rate across all cohorts on the study was 87%. The minimal residual disease negativity rate by flow cytometry was 75%, and IDH1 clearance occurred in 86% of patients who received the triplet combination. The treatment was safe and well tolerated by patients. Researchers are hopeful that these combinations will lead to deeper responses and long-lasting remissions for patients and are currently enrolling patients in the Phase II portion of the trial. Learn more in?

Novel integrated bioinformatics tool may help predict response to immunotherapy
The effectiveness of?immunotherapy?can depend on various factors within the tumor microenvironment, underscoring a need to understand and identify interactions between tumor and immune cells to more accurately predict treatment response. While some bioinformatics tools can help identify immune signatures in tumors, no statistically validated tools are currently capable of examining combinations of tumor-immune interactions. Researchers led by Behnaz Bozorgui, Ph.D., and?, developed an integrated bioinformatics tool, resource and web application ¡ª Immuno-oncology gene interaction Maps (ImogiMap) ¡ª to more efficiently find interactions between tumor cells and immune checkpoints in the tumor microenvironment. Researchers applied the ImogiMap algorithm to?endometrial?and basal-like?breast cancers?to generate novel immune-tumor interactions and actionable targets, which help identify patients most likely to respond to immunotherapy. This tool can also be applied to other types of cancer. Learn more in?.

Recent awards and honors

• , chair of?Investigational Cancer Therapeutics, received the??from the?
• , chair of?Palliative Care Medicine, was inducted into the 2023 Class of?.
• , deputy division head of?Internal Medicine, and?, chair of?Investigational Cancer Therapeutics, were inducted into the?

In case you missed it
Read below to catch up on recent MD Anderson press releases.

• Allison Institute announces appointment of inaugural members
  
• MD Anderson researchers Helen Piwnica-Worms and Richard Wood elected to National Academy of Sciences
• MD Anderson and Generate:Biomedicines enter co-development and commercialization agreement to accelerate novel protein therapeutics for oncology using generative AI
• MD Anderson¡¯s Hagop Kantarjian, M.D., awarded highest honor from American Society of Clinical Oncology

Â鶹ӳ»­ MD Anderson Cancer Center¡¯s Research Highlights provides a glimpse into recent basic, translational and clinical cancer research from MD?Anderson experts. Current advances include new targets involved in protecting DNA replication forks and preventing inflammatory responses, a new treatment option for elderly patients with late-stage acute myeloid leukemia, insights into the breast cancer tumor microenvironment, biomarkers of response to targeted and immune therapies, a novel cellular therapy option for osteosarcoma and a new target for inducing ferroptosis in cancer cells. ?

Proteins involved in protecting DNA replication forks prevent inflammatory response

During DNA replication, a structure known as the replication fork coordinates the unwinding and repair of old and new DNA to minimize genomic instability. Stalls at the fork need to be protected to inhibit DNA degradation and to prevent excessive DNA fragments accumulating outside the nucleus, triggering an inflammatory response. Better understanding this process can identify possible treatment targets for inflammation-related diseases and cancer. To investigate the link, researchers led by Ahmed Emam, Ph.D., and??, generated cells without Abro1 and FANCD2,?two proteins previously shown to be involved in fork protection. Loss of these proteins led to a buildup of cytosolic single-stranded ribosomal DNA, which is detected by the cGAS protein to trigger an immune response. Interestingly, this also led to an increase in P-bodies ¡ª granules that form in response to replication stress ¡ª showing that Abro1 and FANCD2 normally inhibit their production. This study demonstrates the direct role these proteins play in protecting replication forks and inhibiting an innate immune response, highlighting potential therapeutic targets. Learn more in?.?

Enasidenib provides benefit for older AML patients with?IDH2?mutations

IDH2?mutations occur in 8% to 15% of patients with?acute myeloid leukemia (AML), with older patients more likely to have the mutation. In an international Phase III study led by?, researchers compared enasidenib, an oral targeted IDH2 inhibitor, with conventional care regimens (CCR) in patients 60 or older with late-stage,?IDH2-mutant AML that had received 2-3 prior therapies. The trial randomized 319 patients to evaluate the primary endpoint of overall survival (OS). Median OS with enasidenib (6.5 months) and CCR (6.2 months) was not significantly different; however, the one-year survival rate was 37.5% with enasidenib and 26.1%. with conventional care.? Although enasidenib did not lead to significant improvement in median OS, enasidenib provided meaningful benefits in event-free survival, time to treatment failure, overall response rate, hematologic improvement and transfusion independence in this heavily pretreated and older population of patients with?IDH2-mutant AML. This study suggests that enasidenib may be a well-tolerated treatment option for this group of relapsed or refractory patients. Learn more in?.

Profiling the breast cancer immune microenvironment suggests PARP inhibitors may enhance anti-tumor immune response

PARP inhibitors, such as talazoparib, can selectively target?breast cancer?by blocking DNA damage repair in cancer cells. Until now, there hasn¡¯t been a comprehensive look into the tumor immune microenvironment (TiME) to clarify how these PARP inhibitors affect infiltrating immune cells, which would allow for the identification of biomarkers that can harness these pathways. Using pre- and post-treatment samples from 13 patients with?BRCA1/2-mutant breast cancer treated with neoadjuvant talazoparib, Tapsi Kumar, Ph.D.,?, and colleagues profiled the TiME to identify the location of and interactions between immune and tumor cells. While it was a small sample size, they noted phenotypes showing that PARP inhibitor treatment significantly increased infiltrating T cell and cytotoxic T cell density both in the tumor and stroma, suggesting that PARP inhibitors could enhance tumor immunogenicity. This study supports further investigation into combination strategies of PARP inhibitors with?immunotherapy?in?BRCA1/2??-mutant breast cancer. Learn more in?.

Melanoma study discovers potential response biomarkers for combination immunotherapy and targeted therapy

In?BRAF-mutant?melanoma, MEK- and BRAF-targeted therapies?can prime the tumor microenvironment to respond to immunotherapy, emphasizing the potential for combination therapies. The Phase III COMBI-i trial evaluated the addition of?immune checkpoint inhibitor?spartalizumab to BRAF inhibitor dabrafenib and MEK inhibitor trametinib in patients with?BRAF?V600-mutant melanoma. While the study did not meet its primary endpoint of improved progression-free survival, the combination did achieve an objective response rate of 78%, with 16 patients achieving a complete response. To identify patients most likely to benefit from this combination, researchers led by?,?analyzed biomarker data from COMBI-i to explore indicators of treatment response. With over 500 patient tissues, this was one of the largest biomarker data sets from a Phase III trial in melanoma. Baseline detectable circulating tumor DNA emerged as a strong independent prognostic variable, consistent with higher tumor burden and lower T cell inflammation signature. A baseline CD4+/CD8+ T-cell ratio above the median also was potentially predictive of improved response to combination therapy, meriting further investigation. Learn more in the?.

Novel cell therapy suppresses tumor growth and reduces toxicity in osteosarcoma

Chimeric antigen-targeted (CAR) T cell therapy?has not been successful in treating?childhood osteosarcoma. This is due in part to the long expansion time required for T-cells prior to infusion, the lack of T cell infiltration into tumors and T cell exhaustion in tumors post infusion. Molecular variations between tumors and within tumors also make it difficult to use a single type of CAR to target these variable antigens. To confront these complications, researchers led by Qing Yang, M.D., Ph.D., Jiemiao Hu, Ph.D., and?, tested an alternative cell therapy which uses a membrane-anchored and tumor-targeted interleukin-12 (attIL12) to modify peripheral blood mononuclear cells (PBMCs) from fresh blood. Because there is no need for T cell expansion, treatment with attIL12-PBMCs can be done more quickly than CAR T cell therapy. For both?in vivo?and?in vitro?osteosarcoma tumors, attIL12-PBMCs reduced cytokine-associated toxicity and suppressed tumor growth by triggering differentiation of cancer cells into bone-like cells. This study supports further evaluation of attIL12-PBMC cellular therapy in osteosarcoma as a novel treatment option. Learn more in?.

Study discovers novel protein involved in protecting cancer cells from ferroptosis

Ferroptosis is one of several normally occurring pathways that regulate cell death. This process is dependent on iron and protects against the toxic accumulation of lipid peroxides ¡ª the oxidized forms of fatty acids. Understanding how cancer may adapt to block ferroptosis can point to new treatment strategies. In a new study led by Shiqi Wu, Chao Mao, Ph.D., and?, researchers discovered a previously unknown role for the mitochondrial enzyme GPD2 in defending against ferroptosis. To discover this connection, researchers performed a metabolic analysis after blocking another well-known ferroptosis defense protein, GPX4, in cancer cells. They clarified the mechanism of action and demonstrated that inhibiting both GPD2 and GPX4 increased ferroptosis in cell lines. Combined deletion of GPD2 and GPX4 in laboratory models also induced ferroptosis and suppressed tumor growth. The results suggest that inhibiting GPD2 may represent a therapeutic strategy to combat ferroptosis defense mechanisms in cancer. Learn more in?.

Study identifies new biomarkers associated with response to Aurora kinase inhibitors

Some subsets of patients with cancer benefit from treatment with Aurora kinase inhibitors, but there are no available biomarkers to predict which will have a favorable response. Researchers led by Haoyan Li, Ph.D., and?, sought to identify biomarkers associated with improved response to alisertib, an inhibitor selectively targeting Aurora kinase A (AURKA). Using epigenetic screening and drug sensitivity analyses, they discovered that high expression of the CHD1 protein increases sensitivity to alisertib and demonstrated CHD1¡¯s mechanism of action in this response. Additionally, CHD1 is known to be overexpressed in tumors with deficiency in the PTEN tumor suppressor, highlighting PTEN levels as a potential predictive biomarker for AURKA inhibition. This newly discovered role for CHD1?provides further insight into determining which patients will respond positively to alisertib or other AURKA inhibitors. Learn more in?.

In case you missed it

Read below to catch up on recent MD Anderson press releases.

• Poziotinib is active in EGFR exon 20 mutant non-small cell lung cancer with efficacy highly dependent on insertion location