MD Anderson Research Highlights AACR 2024 Special Edition

Featuring combination therapies for AML and lung cancer, insights into treatment resistance, the role of tumor microbiomes in immunity, and improved HPV screening

MD Anderson News Release April 05, 2024

ABSTRACTS: 1212, 1227, 1244, 1283, CT030, 3893, 3922, 3930, 3942, 6620

The University of Texas 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.

This special edition features presentations by MD Anderson researchers at the American Association for Cancer Research (AACR) Annual Meeting 2024. In addition to the studies shown below, forthcoming press releases will feature groundbreaking research on:

  • Combination therapy for KRAS G12C-mutant metastatic colorectal cancer (Abstract CT013)
  • A first-in-class PARP1 inhibitor for patients with advanced cancers marked by specific DNA repair defects (Abstract CT014)
  • Allogeneic chimeric antigen receptor (CAR) T cell therapy for patients with advanced clear cell renal cell carcinoma (Abstract CT002)
  • Oncolytic immunotherapy for solid organ transplant recipients with advanced cutaneous malignancies (Abstract CT003)
  • An antibody-drug conjugate for patients with previously treated advanced gastric or gastroesophageal junction cancer (Abstract CT038)
  • A new combination treatment for patients with relapsed or refractory B-cell non-Hodgkin lymphoma (Abstract CT037)
  • A biomarker-driven targeted therapy combination for patients with DNA damage response mutations (Abstract CT042)

Information on all MD Anderson AACR Annual Meeting content can be found at MDAnderson.org/AACR

Genetic markers predict extended survival with KRAS inhibitors and may identify patients who will benefit from novel combination (Abstract 1212)  
While KRAS G12C inhibitors, such as adagrasib, are revolutionizing advanced non-small cell lung cancer (NSCLC) treatment, there is a need to understand why some patients benefit more than others. In a cohort of 129 patients with advanced KRAS G12C-mutant NSCLC treated with adagrasib, researchers led by Marcelo Negrao, M.D., found that patients whose tumors harbored co-mutations in KEAP1 and/or STK11 had poor clinical outcomes. However, those without the mutations had significantly longer progression-free survival, with a median of 16.8 months. Additionally, combining adagrasib and mTOR inhibitors resulted in higher anti-tumor activity compared to adagrasib alone in KRAS G12C-mutant lung cancer pre-clinical models harboring the co-mutations. The absence of KEAP1 and STK11 co-mutations and low NRF2 transcriptional signature also was found to lower the risk of tumor progression and death by 80% and 90%, respectively, with adagrasib treatment. The safety and efficacy of this combination is under active investigation in the KRYSTAL-19 trial. Negrao will present the study results April 7.

Novel combination overcomes menin inhibitor resistance in mutant AML (Abstract 1227)
Acute myeloid leukemia (AML) with MLL1 rearrangements, which cause MLL1 fusion proteins, usually has dysregulated expression of certain proteins, including HOXA9, MEIS1 and FLT3. Conversely, in NPM1-mutant AML, wild-type MLL1 regulation of those proteins promotes self-renewal and proliferation of myeloid progenitor cells. Although menin inhibitors (MI) have been developed to disrupt the binding of menin and MLL1, reducing HOXA9 and MEIS1 activity, most patients eventually develop treatment resistance or relapse. Researchers led by Kapil Bhalla, M.D., and Warren Fiskus, Ph.D., used whole exome sequencing to determine that this resistance was not due to the presence of menin mutations, but to epigenetic mechanisms. A novel combination targeting epigenetic proteins eliminated AML cells in vivo, overcoming the acquired MI-resistance mechanisms. The study highlights the therapeutic potential of epigenetically targeted agents to overcome resistance to MI. Fiskus will present the findings April 7.

Endogenous retroviruses have therapeutic potential for squamous cancers (Abstract 1244)
Retrotransposons contain parts of ancestral retrovirus genetic elements that are interspersed throughout the human genome and can copy and paste themselves into different locations. Squamous cell carcinoma (SCC) of the skin is the second most common form of skin cancer and resembles SCC in other organs, such as the oral cavity and cervix. These cancers originate in squamous cells that make up the outer layer of these tissues. Abnormal retrotransposon activities frequently occur in cancers, but little is known about their functions. Researchers led by Yejing Ge, Ph.D., discovered a mouse model exhibiting hair loss and a surge of retrotransposon subsets known as endogenous retroviruses. Tumor progression was significantly blocked in this model. The researchers noticed viral-like particles across squamous tissues, suggesting a conserved mechanism for SCCs. Pharmacological or genetic inhibition of this retroviral activity helped to reverse these effects. This study suggests that retrotransposons regulate SCCs, highlighting their therapeutic potential. Ge will present the findings April 7.  

Microbiome may be associated with immune alterations in metastatic brain tumors (Abstract 1283)   
The microbiome plays a prominent role in tumor immunity and treatment response, but how it affects brain tumors or brain metastases is largely unknown. To better understand the relationship, researchers including Golnaz Morad, Ph.D., Jennifer Wargo, M.D., Sherise Ferguson, M.D., and Nadim Ajami, Ph.D., analyzed stool, saliva and tumor samples collected from patients with metastatic brain tumors who underwent surgical tumor resection. The study demonstrated that bacterial signals were detected within metastatic brain tumor cells. There was limited overlap with the gut microbiome, but, instead, the signals were composed mainly of commensal oral bacterial taxa. Examining gene activity in tumor cells uncovered that tumor areas with high bacterial signals were linked to the body's natural defense mechanisms against those bacteria, suggesting an anti-bacterial response within the brain metastases. These results offer new insights into the interactions between cancer, the microbiome and the brain microenvironment, which the authors suggest merit further investigation to improve outcomes for patients with brain tumors. Morad will present the findings April 7. 

Antibiotics affect gut health and immunity in patients with advanced melanoma (Abstract CT030)    
Changing gut bacteria composition may improve immune checkpoint blockade treatment responses, but there are few precision biomarker-driven trials using carefully selected groups of bacteria. To address this, researchers led by Isabella Glitza Oliva, M.D., Ph.D., Jennifer Wargo, M.D., and Yongwoo David Seo, M.D., performed a first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial. The results showed that combining a specific bacterial consortium of Firmicutes spores and Ruminococcaceae, called SER-401, along with anti-PD1 immunotherapy, was safe in patients with advanced melanoma. The Phase Ib MCGRAW study followed 14 patients who received either the oral antibiotic vancomycin plus SER-401, or a placebo followed by nivolumab. The overall response rate in the vancomycin/SER-401 arm was 25% and the disease control rate was 37.5%. While the trial was limited due to poor accrual, pre-conditioning with vancomycin was associated with significant shifts in the microbiome taxonomic composition. The study suggests that antibiotic preconditioning and interventional drug-dosing regimens should be carefully considered when designing such trials. Seo will present updated findings April 8. 

Mapping progression of lung pre-cancer to cancer may point to early interception targets (Abstract 3893)
A deeper understanding of early lung cancer development may offer opportunities for detection and intervention, when treatments are more likely to be effective. To better characterize the evolution from pre-malignant lesions (PMLs) to lung adenocarcinoma (LUAD), Ansam Sinjab, Ph.D., Fuduan Peng, Ph.D., Linghua Wang, M.D., Ph.D., Humam Kadara, Ph.D., and colleagues performed multimodal spatial omics and single-cell sequencing analysis to map molecular profiles, cell states and interactions of matched samples from LUAD, PMLs and normal-appearing tissues adjacent to lesions taken from up to 17 patients. Spatial transcriptomic and proteomic analysis, including RNA-sequencing on more than half a million single cells, revealed that loss of alveolar differentiation and development of alveolar intermediate cells are key features in the progression of PMLs to LUAD. They also noted heterogeneity in abundance and spatial organization of key immune subsets, such as regulatory T cells and B cells, as well as differences in the composition of tertiary lymphoid structures between adjacent normal cells, PMLs and LUAD. This study provides a deeper understanding that could point to targets for the early detection or interception of lung cancer. Sinjab will present the findings April 8.

Study finds key modulators of anti-tumor response in dendritic cells (Abstract 3922)
Dendritic cells trigger an immune response by processing and presenting foreign or invasive antigens on the cell surface for T cell recognition, but the underlying mechanisms for this process are not fully understood. Building upon previous studies in neural stem cells and microglia, Cassian Yee, M.D., Jian Hu, Ph.D., and Yating Li examined the role of RNA-binding protein Quaking (QKI), and its binding partner, PPARδ, in dendritic cells. They found that QKI and PPARδ upregulate genes involved in the formation of phagosomes and endosomes, which enhance phagocytosis. Knocking out QKI or PPARδ reduced CD8 T-cell priming in vitro and accelerated tumor growth in vivo, while limiting the effectiveness of immune checkpoint blockade. The study suggests that QKI and PPARδ are transcriptional regulators of antigen processing and presentation, and it highlights the therapeutic potential of dendritic cells in promoting an antitumor response. Li will present the findings April 8.

New gastric cancer consensus subtypes are linked to patient outcomes (Abstract 3930)
Gastric adenocarcinoma (GAC) is a complex and often fatal form of stomach cancer with diverse genomic characteristics and clinical outcomes. Previous studies have identified various genomic subtypes of GAC, but differences in classification methods have hindered their clinical application. Researchers led by Yun Seong Jeong, Ph.D., and Ju-Seog Lee, Ph.D., integrated and analyzed genomic data from eight previously established genomic subtypes to identify consensus subtypes and assess their clinical implications. Using a cluster of clusters algorithm, they identified six distinct consensus subtypes, each with unique molecular features and clinical outcomes. Notably, the researchers discovered that one subtype, CGS3, displayed heightened sensitivity to radiation therapy, subsequently revealing the underlying biology responsible.  These findings provide a comprehensive classification system for GAC to help guide future clinical trials and personalized treatment strategies, which may ultimately improve outcomes for patients. Jeong will present the results April 8.

At-home HPV testing increased screening among under-screened U.S. patients (Abstract 3942)
Using at-home self-sampling for human papillomavirus (HPV) testing is known to increase the number of people who get screened for cervical cancer among under-screened populations. In the first randomized controlled trial in the U.S. to evaluate the effectiveness of mailed at-home HPV tests in a safety net health system, researchers led by Jane Montealegre Ph.D., found the increase among under-screened American populations jumped more than three-fold when combined with telephone-based patient navigation. The PRESTIS study followed more than 2,270 participants in three arms. Arm 1 received an invitation to usual provider-based screening, Arm 2 was given a phone call and mailed an at-home HPV testing kit, and Arm 3 received a phone call, an at-home kit and telephone-based patient navigation. Screening participation was 15.3%, 44% and 51.4% in the three arms, respectively. Participants were predominantly Hispanic (68.6%) and uninsured, with a mean age of 47.9 years. This study suggests that Food and Drug Administration approval of self-sampling for HPV testing may dramatically increase participation in cervical cancer screening in underserved populations. Trisha Amboree, Ph.D., will present the findings April 8.   

New triple-negative breast cancer models help identify vulnerabilities in chemotherapy-resistant disease (Abstract 6620)
Chemotherapy is the standard treatment for triple-negative breast cancer (TNBC) but, while many patients respond well, some with significant cancer remaining after treatment face high risks of recurrence. To understand why some tumors resist therapy, researchers led by Amanda Rinkenbaugh, Ph.D., and Helen Piwnica-Worms, Ph.D., created 92 TNBC models from patient tumors before, during and after chemotherapy. They found that models from treatment-resistant tumors were more successfully grafted. These models represent the diversity associated with TNBC, with most developing lung metastases. Genetic analysis showed similarities between patient tumors and models, with the TP53 gene, in particular, being the most commonly mutated. Drug testing on these models identified vulnerabilities in resistant tumors, suggesting possible new treatment targets. Studies with pevonedistat identified its effectiveness against chemotherapy-resistant TNBC. This study provides insights into chemotherapy resistance and opens avenues for targeted therapies to improve outcomes for patients with TNBC. Rinkenbaugh will present these results April 9.