bims-almceb 2021-09-19 papers

Blood. 2021 Sep 15. pii: blood.2021013201. [Epub ahead of print]

The STAT3-MYC Axis Promotes Survival of Leukemia Stem Cells by Regulating SLC1A5 and Oxidative Phosphorylation.

Maria Amaya, Anagha Inguva, Shanshan Pei, Courtney L Jones, Anna Krug, Haobin Ye, Mohammad Minhajuddin, Amanda C Winters, Steffanie L Furtek, Fabia Gamboni, Brett M Stevens, Angelo D'Alessandro, Daniel A Pollyea, Philip Reigan, Craig T Jordan.

AML is characterized by the presence of leukemia stem cells (LSCs), and failure to fully eradicate this population contributes to disease persistence/relapse. Prior studies have characterized metabolic vulnerabilities of LSCs, which demonstrate preferential reliance on oxidative phosphorylation (OXPHOS) for energy metabolism and survival. In the present study, using both genetic and pharmacologic strategies in primary human AML specimens, we show that signal transducer and activator of transcription 3 (STAT3) mediates OXPHOS in LSCs. STAT3 regulates AML-specific expression of MYC, which in turn controls transcription of the neutral amino acid transporter SLC1A5. We show that genetic inhibition of MYC or SLC1A5 acts to phenocopy the impairment of OXPHOS observed with STAT3 inhibition, thereby establishing this axis as a regulatory mechanism linking STAT3 to energy metabolism. Inhibition of SLC1A5 reduces intracellular levels of glutamine, glutathione and multiple TCA metabolites, leading to reduced TCA cycle activity and inhibition of OXPHOS. Based on these findings, we used a novel small molecule STAT3 inhibitor, that binds STAT3 and disrupts STAT3-DNA, to evaluate the biological role of STAT3. We show that STAT3 inhibition selectively leads to cell death in AML stem and progenitor cells derived from newly diagnosed and relapsed patients, while sparing normal hematopoietic cells. Together, these findings establish a STAT3-mediated mechanism that controls energy metabolism and survival in primitive AML cells.

DOI: https://doi.org/10.1182/blood.2021013201

Cell Chem Biol. 2021 Sep 11. pii: S2451-9456(21)00363-9. [Epub ahead of print]

Targeted epigenetic induction of mitochondrial biogenesis enhances antitumor immunity in mouse model.

Madhu Malinee, Ganesh Namasivayam Pandian, Hiroshi Sugiyama.

Considering the potential of combinatorial therapies in overcoming existing limitations of cancer immunotherapy, there is an increasing need to identify small-molecule modulators of immune cells capable of augmenting the effect of programmed cell death protein 1 (PD-1) blockade, leading to better cancer treatment. Although epigenetic drugs showed potential in combination therapy, the lack of sequence specificity is a major concern. Here, we identify and develop a DNA-based epigenetic activator with tri-arginine vector called EnPGC-1 that can trigger the targeted induction of the peroxisome proliferator-activated receptor-gamma coactivator 1 alpha/beta (PGC-1α/β), a regulator of mitochondrial biogenesis. EnPGC-1 enhances mitochondrial activation, energy metabolism, proliferation of CD8+ T cells in vitro, and, in particular, enhances oxidative phosphorylation, a feature of long-lived memory T cells. Genome-wide gene analysis suggests that EnPGC-1 and not the control compounds can regulate T cell activation as a major biological process. EnPGC-1 also synergizes with PD-1 blockade to enhance antitumor immunity and improved host survival.

Keywords: PD-1; T-cell activation; cancer immunotherapy; combination therapy; epigenetic activator; mitochondrial biogenesis; oxidative phosphorylation; pyrrole-imidazole polyamide; therapeutic gene modulation

DOI: https://doi.org/10.1016/j.chembiol.2021.08.001

Aging (Albany NY). 2021 Sep 11. undefined(undefined):

Aging, stem cells and cancer updated.

Osama A Elkashty, Arvind Hariharan, Simon D Tran.

Keywords: cancer stem cells; epigenetic; head and neck cancer; signaling pathways; tumorigenesis

DOI: https://doi.org/10.18632/aging.203535

Cancer Res. 2021 Sep 16. pii: canres.1606.2021. [Epub ahead of print]

Epigenetic alterations and mechanisms that drive resistance to targeted cancer therapies.

Narendra Wajapeyee, Romi Gupta.

Cancer is a complex disease and cancer cells typically harbor multiple genetic and epigenetic alterations. Large-scale sequencing of patient-derived cancer samples has identified several druggable driver oncogenes. Many of these oncogenes can be pharmacologically targeted to provide effective therapies for breast cancer, leukemia, lung cancer, melanoma, lymphoma, and other cancer types. Initial responses to these agents can be robust in many cancer types and some cancer patients experience sustained tumor inhibition. However, resistance to these targeted therapeutics frequently emerges, either from intrinsic or acquired mechanisms, posing a major clinical hurdle for effective treatment. Several resistance mechanisms, both cell autonomous and cell non-autonomous, have been identified in different cancer types. Here we describe how alterations of the transcriptome, transcription factors, DNA, and chromatin regulatory proteins confer resistance to targeted therapeutic agents. We also elaborate on how these studies have identified underlying epigenetic factors that drive drug resistance and oncogenic pathways, with direct implications for the prevention and treatment of drug-resistant cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-1606

J Geriatr Oncol. 2021 Sep 11. pii: S1879-4068(21)00208-3. [Epub ahead of print]

Patient-reported outcomes predict overall survival in older patients with acute myeloid leukemia.

John Devin Peipert, Fabio Efficace, Renee Pierson, Christina Loefgren, David Cella, Jianming He.

INTRODUCTION: Patient-reported outcomes (PROs) predict overall survival (OS) in many cancer types, but there is little evidence of their prognostic value in older patients with acute myeloid leukemia (AML). We examined whether the Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) predicted OS beyond established prognostic factors among these patients.
MATERIALS AND METHODS: Data were from AML2002 (n = 309), a randomized phase 2/3 study comparing decitabine plus talacotuzumab versus decitabine alone in older AML patients ineligible for intensive chemotherapy. We used ridge-penalized Cox proportional hazards models to estimate the association between baseline FACT-Leu scales and OS. We then conducted a bootstrap analysis to determine how often FACT-Leu scales appeared in forward- and backward- selected "final models" predicting OS relative to prognosticators from the AML Composite Model (AML-CM; e.g., chronic comorbidities, previous cancer, cytogenetic/molecular risk).
RESULTS: In ridge-penalized models, the FACT-Leu Physical Well-Being (PWB), Trial Outcomes Index (TOI), and Total scales predicted OS. Adjusting for AML-CM factors, an important increase (3 points) in PWB score was associated with a 14% reduction in the hazard of death. In the bootstrap analysis, the PWB scale appeared in 93% of backward- and 98% of forward selected models, while the TOI [57% (backward), 79% (forward)] and FACT-Leu Total [51% (backward), 78% (forward)] appeared less often in final models.
DISCUSSION AND CONCLUSIONS: These results indicate PROs' value for predicting outcomes among older AML patients and underscore the need to more systematically collect PRO data in routine care with these patients. ClinicalTrials.gov Registration: NCT02472145.

Keywords: Acute myeloid leukemia; FACT-Leu; Health related quality of life; Overall survival

DOI: https://doi.org/10.1016/j.jgo.2021.09.007

Front Immunol. 2021 ;12 733136

PD-1 Blockade on Tumor Microenvironment-Resident ILC2s Promotes TNF-α Production and Restricts Progression of Metastatic Melanoma.

Emily Howard, Benjamin P Hurrell, Doumet Georges Helou, Christine Quach, Jacob D Painter, Pedram Shafiei-Jahani, Marshall Fung, Parkash S Gill, Pejman Soroosh, Arlene H Sharpe, Omid Akbari.

While pulmonary ILC2s represent one of the major tissue-resident innate lymphoid cell populations at steady state and are key drivers of cytokine secretion in their occupational niche, their role in pulmonary cancer progression remains unclear. As the programmed cell death protein-1 (PD-1) plays a major role in cancer immunotherapy and immunoregulatory properties, here we investigate the specific effect of PD-1 inhibition on ILC2s during pulmonary B16 melanoma cancer metastasis. We demonstrate that PD-1 inhibition on ILC2s suppresses B16 tumor growth. Further, PD-1 inhibition upregulates pulmonary ILC2-derived TNF-α production, a cytotoxic cytokine that directly induces cell death in B16 cells, independent of adaptive immunity. Together, these results highlight the importance of ILC2s and their anti-tumor role in pulmonary B16 cancer progression during PD-1 inhibitory immunotherapy.

Keywords: PD-1; TNF - α; cancer; innate lymphoid cell 2; melanoma

DOI: https://doi.org/10.3389/fimmu.2021.733136