Staphylococcus aureus induces drug resistance in cancer T cells in Sézary syndrome.

ABSTRACT: Patients with Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), are prone to Staphylococcus aureus infections and have a poor prognosis due to treatment resistance. Here, we report that S aureus and staphylococcal enterotoxins (SE) induce drug resistance in malignant T cells against therapeutics commonly used in CTCL. Supernatant from patient-derived, SE-producing S aureus and recombinant SE significantly inhibit cell death induced by histone deacetylase (HDAC) inhibitor romidepsin in primary malignant T cells from patients with SS. Bacterial killing by engineered, bacteriophage-derived, S aureus-specific endolysin (XZ.700) abrogates the effect of S aureus supernatant. Similarly, mutations in major histocompatibility complex (MHC) class II binding sites of SE type A (SEA) and anti-SEA antibody block induction of resistance. Importantly, SE also triggers resistance to other HDAC inhibitors (vorinostat and resminostat) and chemotherapeutic drugs (doxorubicin and etoposide). Multimodal single-cell sequencing indicates T-cell receptor (TCR), NF-κB, and JAK/STAT signaling pathways (previously associated with drug resistance) as putative mediators of SE-induced drug resistance. In support, inhibition of TCR-signaling and Protein kinase C (upstream of NF-κB) counteracts SE-induced rescue from drug-induced cell death. Inversely, SE cannot rescue from cell death induced by the proteasome/NF-κB inhibitor bortezomib. Inhibition of JAK/STAT only blocks rescue in patients whose malignant T-cell survival is dependent on SE-induced cytokines, suggesting 2 distinct ways SE can induce drug resistance. In conclusion, we show that S aureus enterotoxins induce drug resistance in primary malignant T cells. These findings suggest that S aureus enterotoxins cause clinical treatment resistance in patients with SS, and antibacterial measures may improve the outcome of cancer-directed therapy in patients harboring S aureus.

Entinostat in patients with relapsed or refractory abdominal neuroendocrine tumors.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare neoplasms with an increasing annual incidence and prevalence. Many are metastatic at presentation or recur following surgical resection and require systemic therapy, for which somatostatin analogs such as octreotide or lanreotide comprise typical first-line therapies. Nonetheless, treatment options remain limited. Epigenetic processes such as histone modifications have been implicated in malignant transformation and progression. In this study, we evaluated the anti-proliferative effects of a histone deacetylase (HDAC) inhibitor, entinostat, which was computationally predicted to show anti-cancer activity, as confirmed in in vitro and in vivo models of GEP-NETs. METHODS: This was a phase II study to evaluate the efficacy and safety of entinostat in patients with relapsed or refractory abdominal NETs. The primary objective was to estimate the objective response rate to entinostat. Additionally, with each patient as his/her own control we estimated the rates of tumor growth prior to enrollment on study and while receiving entinostat. Patients received 5 mg entinostat weekly until disease progression or intolerable toxicity. The dose could be changed to 10 mg biweekly for patients who did not experience grade ≥ 2 treatment-related adverse events (AEs) in cycle 1, but was primarily administered at the starting 5 mg weekly dose. RESULTS: The study enrolled only 5 patients due to early termination by the drug sponsor. The first patient that enrolled had advanced disease and died within days of enrollment before follow-up imaging due to a grade 5 AE unrelated to study treatment and was considered non-evaluable. Best RECIST response for the remaining 4 patients was stable disease (SD) with time on study of 154+, 243, 574, and 741 days. With each patient as his/her own control, rates of tumor growth on entinostat were markedly reduced with rates 20%, 33%, 54%, and 68% of the rates prior to enrollment on study. Toxicities possibly or definitely related to entinostat included grade 2/3 neutrophil count decrease [2/4 (50%)/ 2/4 (50%)], grade 3 hypophosphatemia [1/4, (25%)], grade 1/2 fatigue [1/4 (25%)/ 2/4 (50%)], and other self-limiting grade 1/2 AEs. CONCLUSION: In the treatment of relapsed or refractory abdominal NETs, entinostat 5 mg weekly led to prolonged SD and reduced the rate of tumor growth by 32% to 80% with an acceptable safety profile (ClinicalTrials.gov Identifier: NCT03211988).

Beyond BRCA: Diagnosis and management of homologous recombination repair deficient pancreatic cancer.

Approximately 4%-7% of patients diagnosed with pancreatic adenocarcinoma (PDAC) are found to harbor deleterious germline mutations in BRCA1 and/or BRCA2. Loss of function of BRCA1 and/or BRCA2 results in deficiency in homologous recombination repair (HRR), a critical DNA repair pathway, and confers sensitivity to certain DNA damaging agents, including platinum chemotherapy and PARP inhibitors. The PARP inhibitor olaparib is food and drug administration (FDA) approved for use in pancreatic cancer based on the POLO trial, which found that maintenance olaparib significantly prolonged progression free survival compared to placebo among patients with germline BRCA1 or BRCA2 mutations and metastatic PDAC that had not progressed following frontline platinum-based chemotherapy. Recently, there has been considerable interest in identifying patients without BRCA inactivation whose tumors also exhibit properties of HRR deficiency and thus may be susceptible to therapies with proven benefit in cancers harboring BRCA mutations. Here, we discuss methods for identification of HRR-deficiency and review the management of HRR-deficient cancers with a focus on HRR-deficient PDAC.

Combined HDAC and eIF4A inhibition: A novel epigenetic therapy for pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma-(PDAC) needs innovative approaches due to its 12% 5-year survival despite current therapies. We show marked sensitivity of pancreatic cancer cells to the combination of a novel eIF4A inhibitor, des-methyl pateamine A (DMPatA), and a histone deacetylase inhibitor, romidepsin, inducing epigenetic reprogramming as an innovative therapeutic strategy. Exploring the mechanistic activity of this combination showed that with a short duration of romidepsin at low doses, robust acetylation persisted up to 48h with the combination, while histone acetylation rapidly faded with monotherapy. This represents an unexpected mechanism of action against PDAC cells that triggers transcriptional overload, metabolic stress, and augmented DNA damage. Structurally different class I HDAC inhibitors exhibit the same hyperacetylation patterns when co-administered with DMPatA, suggesting a class effect. We show efficacy of this combination regimen against tumor growth in a MIA PaCa-2 xenograft model of PDAC with persistent hyperacetylation confirmed in tumor samples. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma, a significant clinical challenge, could benefit from the latent potential of epigenetic therapies like HDAC inhibitors-(HDIs), typically limited to hematological malignancies. Our study shows that a synergistic low dose combination of HDIs with an eIF4A-inhibitor in pancreatic cancer models results in marked pre-clinical efficacy, offering a promising new treatment strategy.

Assessment of PSA responses and changes in the rate of tumor growth (g-rate) with immune checkpoint inhibitors in US Veterans with prostate cancer.

We examined data from US Veterans with prostate cancer (PC) to assess disease response to immune checkpoint inhibitors (ICI) as monotherapy or combined with abiraterone or enzalutamide to assess ICI efficacy in the real-world. We queried the VA corporate data warehouse (CDW) to identify Veterans with a diagnosis of PC who received ICI for any malignancy and had ≥1 PSA measurement while receiving ICI. To evaluate ICI monotherapy, we restricted analysis to Veterans who had not received LHRH agonists/antagonists, PC-directed medical therapy, or radiation/extirpative surgery of the bladder/prostate within and preceding the duration of ICI administration. For ICI combination analysis, we identified Veterans who received abiraterone or enzalutamide for PC while on ICI. We calculated rates of tumor (PSA) growth (g-rates), comparing them to a 1:2 matched reference cohort. We identified 787 Veterans with PC and ≥1 PSA measurement while receiving an ICI. Median duration of ICI therapy was 155 days. 223 Veterans received ICI monotherapy, with only 17(8%) having a reduction in PSA (median decline = 43%). 12 (5%) had PSA declines >30% (PSA30) which included 6 (3%) who had PSA reductions greater than 50% (PSA50). Median g-rates for ICI plus abiraterone (n = 20) or enzalutamide (n = 31) were 0.000689/d-1 and 0.002819/d-1, respectively, and were statistically insignificant compared to g-rates of matched cohorts receiving abiraterone (g = 0.000925/d-1, P = 0.73) or enzalutamide (g = 0.001929/d-1, P = 0.58) alone. Our data align with clinical trial data in PC, demonstrating limited benefit from ICI monotherapy and predicting no survival benefit from simultaneous abiraterone or enzalutamide with an ICI using g-rate.

The Methyltransferases METTL7A and METTL7B Confer Resistance to Thiol-Based Histone Deacetylase Inhibitors.

Histone deacetylase inhibitors (HDACi) are part of a growing class of epigenetic therapies used for the treatment of cancer. Although HDACis are effective in the treatment of T-cell lymphomas, treatment of solid tumors with this class of drugs has not been successful. Overexpression of the multidrug resistance protein P-glycoprotein (P-gp), encoded by ABCB1, is known to confer resistance to the HDACi romidepsin in vitro, yet increased ABCB1 expression has not been associated with resistance in patients, suggesting that other mechanisms of resistance arise in the clinic. To identify alternative mechanisms of resistance to romidepsin, we selected MCF-7 breast cancer cells with romidepsin in the presence of the P-gp inhibitor verapamil to reduce the likelihood of P-gp-mediated resistance. The resulting cell line, MCF-7 DpVp300, does not express P-gp and was found to be selectively resistant to romidepsin but not to other HDACis such as belinostat, panobinostat, or vorinostat. RNA-sequencing analysis revealed upregulation of the mRNA coding for the putative methyltransferase, METTL7A, whose paralog, METTL7B, was previously shown to methylate thiol groups on hydrogen sulfide and captopril. As romidepsin has a thiol as the zinc-binding moiety, we hypothesized that METTL7A could inactivate romidepsin and other thiol-based HDACis via methylation of the thiol group. We demonstrate that expression of METTL7A or METTL7B confers resistance to thiol-based HDACis and that both enzymes are capable of methylating thiol-containing HDACis. We thus propose that METTL7A and METTL7B confer resistance to thiol-based HDACis by methylating and inactivating the zinc-binding thiol.