Conventional Combination Chemotherapy Research Articles

A β-Carboline Derivate PAD4 Inhibitor Reshapes Neutrophil Phenotype and Improves the Tumor Immune Microenvironment against Triple-Negative Breast Cancer.

Triple-negative breast cancer is a highly aggressive and heterogeneous breast cancer subtype characterized by early metastasis, poor prognosis, and high recurrence. Targeting histone citrullination-mediated chromatin dysregulation to induce epigenetic alterations shows great promise in TNBC therapy. We report the synthesis, optimization, and evaluation of a novel series of β-carboline-derived peptidyl arginine deiminase 4 inhibitors that exhibited potent inhibition of TNBC cell proliferation. The most outstanding PAD4 inhibitor, compound 28, hindered the PAD4-H3cit-NET signaling pathway and inhibited the growth of solid tumors and pulmonary metastatic nodules in the 4T1 in situ mouse model. Furthermore, 28 improved the tumor immune microenvironment by reshaping neutrophil phenotype, upregulating the proportions of dendritic cells and M1 macrophages, and reducing the amount of myeloid-derived suppressor cells. In conclusion, our work offered 28 as an efficacious PAD4 inhibitor that exerts a combination of conventional chemotherapy and immune-boosting effects, which represents a potential therapy strategy for TNBC.

Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and tumor progression of clear cell ovarian cancer

Ovarian clear cell carcinoma (OCCC) is a gynecological cancer with a dismal prognosis; however, the mechanism underlying OCCC chemoresistance is not well understood. To explore the intracellular networks associated with the chemoresistance, we analyze surgical specimens by performing integrative analyses that combine single-cell analyses and spatial transcriptomics. We find that a chemoresistant OCCC subpopulation with elevated HIF activity localizes mainly in areas populated by cancer-associated fibroblasts (CAFs) with a myofibroblastic phenotype, which is corroborated by quantitative immunostaining. CAF-enhanced chemoresistance and HIF-1α induction are recapitulated in co-culture assays, which show that cancer-derived platelet-derived growth factor (PDGF) contributes to the chemoresistance and HIF-1α induction via PDGF receptor signaling in CAFs. Ripretinib is identified as an effective receptor tyrosine kinase inhibitor against CAF survival. In the co-culture system and xenograft tumors, ripretinib prevents CAF survival and suppresses OCCC proliferation in the presence of carboplatin, indicating that combination of conventional chemotherapy and CAF-targeted agents is effective against OCCC.

Comparison of Tepotinib, Paclitaxel, or Ramucirumab Efficacy According to the Copy Number or Phosphorylation Status of the MET Gene: Doublet Treatment versus Single Agent Treatment.

Although conventional combination chemotherapies for advanced gastric cancer (GC) increase survival, such therapies are associated with major adverse effects; more effective and less toxic treatments are required. Combinations of different anti-cancer drugs, for example, paclitaxel plus ramucirumab, have recently been used as second-line treatments for advanced GC. This study evaluated how copy number variations of the MET gene, MET mutations, and MET gene and protein expression levels in human GC cells modulate the susceptibility of such cells to single-agent (tepotinib, ramucirumab, or paclitaxel) and doublet (tepotinib-plus-paclitaxel or ramucirumab-plus-paclitaxel treatment regimens. Compared with ramucirumab-plus-paclitaxel, tepotinib-plus-paclitaxel better inhibited the growth of GC cells with MET exon 14 skipping mutations and those lacking MET amplification but containing phosphorylated MET; such inhibition was dose-dependent and associated with cell death. Tepotinib-plus-paclitaxel and ramucirumab-plus-paclitaxel similarly inhibited the growth of GC cells lacking MET amplification or MET phosphorylation, again in a dose-dependent manner, but without induction of cell death. However, tepotinib alone or tepotinib-plus-ramucirumab was more effective against c-MET-positive GC cells (>30 copy number variations) than was ramucirumab or paclitaxel alone or ramucirumab-plus-paclitaxel. These in vitro findings suggest that compared with ramucirumab-plus-paclitaxel, tepotinib-plus-paclitaxel better inhibits the growth of c-MET-positive GC cells, cells lacking MET amplification but containing phosphorylated MET, and cells containing MET mutations. Clinical studies are required to confirm the therapeutic effects of these regimens.

Efficacy of photodynamic therapy using hematoporphyrin derivative nanomedicine on hepatocellular carcinoma cells.

Objective: To demonstrate the efficacy of photodynamic therapy (PDT) using hematoporphyrin derivative (HPD) nanomedicine in combination with conventional chemotherapy based on gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) magnetic resonance imaging (MRI) for hepatocellular carcinoma (HCC) therapy. Methods: HPD nanomedicine was prepared, and the cytotoxicity of HPD nanomedicine at different concentrations on HCC cells and the half-maximal inhibitory concentration (IC50) were analyzed. Sixty HCC patients who visited our hospital from 2021 to 2023 were retrospectively analyzed. Patient data were analyzed, with 30 cases in control group (CG) receiving conventional chemotherapy for HCC, and 30 cases in observation group (OG) receiving conventional chemotherapy combined with HPD nanomedicine PDT. Gd-DTPA MRI was utilized to monitor the morphological and biological characteristics of the lesions in patients. After treatment completion, the long-term efficacy of patients and the levels of bcl-2 and bax proteins in primary HCC cells were evaluated. Results: The IC50 values of HPD on HepG2 cell proliferation and the cell inhibition rates gradually increased with increasing doses of HPD (50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.13 μM, 1.56 μM, 0.78 μM). HPD exhibited great anti-proliferative effects on HepG2 cells at relatively low concentrations. The differences in expression rates of bcl-2 protein and bax protein between groups were considerable (P<0.05). There were neglectable changes in AST and ALT levels between the two groups before treatment, but they were markedly reduced after treatment versus before treatment (P<0.05), with OG showing considerably lower levels than CG after treatment (P<0.05). Additionally, patients in OG exhibited better survival rates after the course of treatment versus those in CG. Conclusion: This study demonstrates that the combination of conventional chemotherapy based on Gd-DTPA MRI with HPD nanomedicine PDT greatly improves the efficacy of treatment for HCC patients. This combined treatment strategy not only enhances therapeutic outcomes but also alleviates adverse reactions associated with conventional treatment, providing a novel approach for future research in the treatment of HCC.

Brentuximab Vedotin in Frontline Therapy of Hodgkin Lymphoma in Patients with Significant Comorbidities Ineligible for Standard Chemotherapy (SGN35-015 Part E)

Brentuximab vedotin (BV) is approved for the treatment of adults with treatment-naïve stage III or IV classical Hodgkin lymphoma (cHL) combined with doxorubicin, vinblastine, and dacarbazine (AVD) and targets CD30, a receptor expressed on the Reed Sternberg cells. Treatment with BV plus AVD has demonstrated improved overall survival (OS) (6-year OS estimate of 93.9% vs 89.4%; HR, 0.59; 95% CI, 0.40-0.88; P=0.009) compared with the standard chemotherapy combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (Ansell 2022). For patients (pts) newly diagnosed with cHL, current treatment options have improved pt outcomes in recent years, but survival rates are still very low for those with significant comorbidities. Pts with comorbid conditions can have poor outcomes due to decreased ability to tolerate dose intensity, increased treatment-related toxicity, and cHL relapse. This study is evaluating the efficacy and safety of single-agent BV as frontline therapy in cHL pts who are ineligible for conventional combination chemotherapy because of comorbidities. SGN35-015 Part E (NCT01716806) was a phase 2, open-label study of BV as frontline cHL therapy. Eligible pts (≥18 years) were unfit for initial conventional combination chemotherapy for cHL as documented by a modified Cumulative Illness Rating Scale score ≥10 or because they required or depended on others for instrumental activities of daily living. Pts received BV (1.8 mg/kg) on Day 1 of each 3-week cycle for up to 16 cycles. Granulocyte colony-stimulating factor prophylaxis was not required. The primary endpoint, objective response rate (ORR), was assessed by Blinded Independent Central Review (BICR) according to the Modified Lugano Criteria (Cheson 2014). Key secondary endpoints included safety, duration of response (DOR), complete response (CR) rate using the Lugano Criteria (Cheson 2014), duration of CR, progression-free survival (PFS), and OS. Thirty pts with cHL received BV and the median age was 76 years (range, 54 to 93 years). Most pts were female (53%) and had a disease stage of II (37%) or III (37%), an Eastern Cooperative Oncology Group (ECOG) performance status of ≥2 (50%; 10 pts [33%] and 5 pts [17%] had an ECOG performance status of 2 and 3, respectively). The median treatment duration was 18 weeks (range, 1 to 50 weeks). Per BICR, the ORR was 60% (18/30) (95% CI: 40.6%, 77.3%), including 33% (10/30) with a CR and 27% (8/30) with a partial response. Six pts (20%) did not respond to treatment: 1 (3%) with progressive disease and 5 (17%) with stable disease; one pt (3%) was not evaluable and the remaining 5 pts (17%) did not have postbaseline responses, either because of death before first scheduled response assessment or not yet reaching the first scheduled response assessment. Median DOR was 7.4 months (95% CI: 7.4 months, not estimable) and median PFS was 8.7 months (95% CI: 5.1 months, not estimable). Median duration of CR was not estimable (95% CI: 7.4 months, not estimable). With a median follow-up of 14.6 months (range, 0 to 44 months), the 2-year OS rate was 70% (95% CI: 48%, 84%). A total of 18 pts (60%) experienced grade ≥3 treatment-emergent adverse events (TEAEs). The most common grade ≥3 TEAEs were fatigue (n=3; 10%), acute kidney injury, anemia, atrial fibrillation, back pain, gait disturbance, hypoxia, neutrophil count decreased, pneumonia, sepsis, syncope, and vomiting (n=2 each; 7%). Nine pts (30%) discontinued treatment because of a TEAE; 1 death due to a TEAE (failure to thrive) was considered treatment-related. Thirteen percent (n=4) of pts experienced grade ≥3 peripheral neuropathy. In pts with cHL who are unfit for initial conventional chemotherapy due to comorbidities, BV monotherapy as frontline treatment appears effective, has an acceptable safety profile, and despite the small sample size could be considered as an option for pts with cHL who are unfit for conventional chemotherapy.

Abstract 1082: Effect of doublet treatment versus single-agent treatment in gastric cancers with/without MET amplification or a MET exon 14 skipping mutation

Abstract Although conventional combination chemotherapy for advanced gastric cancer (GC) is associated with increased survival, it has major adverse effects, which necessitate the development of more effective, less toxic treatments. Combinations of multiple anti-cancer drugs, such as paclitaxel plus ramucirumab, have recently been used for the second-line treatment of advanced GC. This study evaluated the MET copy number variation (CNV), mutations, and gene and protein expression in human GC cells and the differential susceptibility of GC cells to single (tepotinib, ramucirumab, or paclitaxel) or doublet (tepotinib plus paclitaxel or ramucirumab plus paclitaxel) regimens. Compared to ramucirumab plus paclitaxel, tepotinib plus paclitaxel inhibited the growth of GC cells with a MET exon 14 skipping mutation and those without MET amplification but with phosphorylated MET in a dose-dependent manner with a concomitant induction of cell death. Tepotinib plus paclitaxel and ramucirumab plus paclitaxel similarly inhibited the growth of GC cells without a MET amplification or MET phosphorylation in a dose-dependent manner without inducing cell death. However, tepotinib alone or tepotinib plus ramucirumab was more effective in c-MET-positive GC cells (CNV &amp;gt; 30) than ramucirumab alone, paclitaxel alone, or ramucirumab plus paclitaxel. Our in vitro findings suggest that, compared to ramucirumab plus paclitaxel, tepotinib plus paclitaxel inhibits the growth of c-MET-positive GC cells, GC cells without a MET amplification but with phosphorylated MET, and those with MET mutations. Tepotinib alone was as effective as tepotinib plus paclitaxel in c-MET-positive GC cells. Clinical studies are required to confirm the therapeutic effects of these regimens. Citation Format: Dae Young Zang, sung-hwa sohn, Hee Jung Sul, Bum Jun Kim. Effect of doublet treatment versus single-agent treatment in gastric cancers with/without MET amplification or a MET exon 14 skipping mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1082.

P388: PREFERENTIAL SYNERGISTIC EFFECT OF INDISULAM IN COMBINATION WITH VENETOCLAX AND AZACYTIDINE IN AML CELLS WITH SF3B1 MUTATIONS.

Background: Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor prognosis characterized by a high rate of relapse after conventional combination chemotherapy, highlighting the need for improved therapeutic interventions. Genes involved in pre-mRNA splicing, namely SF3B1, U2AF1 and SRSF2, are frequently mutated in AML.Recent studies suggest that pharmacological targeting of the splicing machinery results in preferential lethality of splicing mutant AML cells, potentially providing a novel strategy for treatment of this disease. Existing anti- cancer sulfonamides have been shown to interfere with splicing and induce preferential killing of splicing mutant AML cell lines. A particular sulfonamide drug, indisulam, was previously studied in cancer clinical trials where it was found to be safe but demonstrated limited efficacy, most likely because neither the mechanism of action nor potential biomarkers of response were known. Aims: We investigated, in this study, the efficacy of indisulam, either alone or in combination with ABT-199 (venetoclax) and azacitidine, in cultured primary human AML cells. Methods: Bone marrow cells were collected from adults newly diagnosed with AML, non-treated. Cells were cultured and incubated for 48 and 72 hours with indisulam at a range of nanomolar concentrations. Additionally, cells were incubated with ABT-199 (10nM) and azacitidine (1μM), alone or in combination with indisulam. Cell viability and cell death were measured. For mutation profiling, a targeted myeloid gene panel was used. Results: We found that treatment with indisulam resulted in lethality of primary AML cells harboring mutations in SF3B1, but had minor or no effect on AML cells with other mutations including mutations in splicing factors U2AF1 and SRSF2. In SF3B1-mutated cells, a clear synergistic effect was further observed when indisulam was combined with ABT-199 and azacitidine. The correlation between efficacy of indisulam and synergy with ABT-199 and azacitidine in AML cells with different mutations will be shown and discussed. Summary/Conclusion: Our results indicate that indisulam is preferentially active and synergistic with venetoclax and azacitidine in SF3B1-mutated cells from newly diagnosed, non-treated AML patients.

The synergistic anticancer effect of salinomycin combined with cabazitaxel in CD44+ prostate cancer cells by downregulating wnt, NF-κB and AKT signaling.

Tumor-initiating or cancer stem cells (CSCs) reduce the effectiveness of conventional therapy. Thus, it is crucial to eliminate CSCs while killing bulky cancer cells using a combination of conventional chemotherapy and anti-CSC drugs. Salinomycin is a selective inhibitor against CSCs and shows promise in combination applications. The aim of the study was to examine the efficacy of co-administered cabazitaxel and salinomycin on the survival of prostate cancer cells and CSCs. CD44 + stem cells were isolated from human PC3 prostate cancer cells by using magnetic activated cell sorting. The cells were concomitantly exposed to salinomycin and cabazitaxel, and the cell survival was determined by MTT test. Apoptosis was assessed by image-based cytometer, and cell migration was evaluated by wound healing assay. The expression of target mRNA and protein were assessed by RT-qPCR and Western blot, respectively. Combination index (CI) analysis showed that simultaneous administration of salinomycin and cabazitaxel was able to exert strong synergistic effect on CD44 + subpopulation (CI = 0.33), but no synergism was observed in PC3 cells. The combination of the two agents significantly increased Bax, cytochrome c, caspase-3 and - 8 mRNA expression in CD44 + CSCs, causing apoptosis. The applied therapy strategy strongly inhibited the phosphorylation of Akt, protein expression of Akt1, NF-κB and Wnt. In conclusion, our data suggest that combining salinomycin with cabazitaxel shows promise as a prostate cancer treatment approach that can target CSCs.

NUT carcinoma in children, adolescents and young adults

NUT carcinoma (NC), defined by the presence of the NUTM1 rearrangement, is an aggressive tumour associated with poor prognosis. This rare cancer is underdiagnosed and difficult to treat. The primary objective of this review is to describe the clinical, radiological and laboratory features of NC in young patients. The secondary objective is to propose a consensual strategy for the French very Rare Tumour group (FRACTURE group). NUT-specific antibody immunostaining in cases of undifferentiated or poorly differentiated carcinoma may demonstrate the specific NUT gene rearrangement. NCs are frequently advanced stage at diagnosis and the outcome remains poor despite a global strategy that generally includes conventional combination chemotherapy with wide local therapy (surgery, radiotherapy). Chemosensitivity is frequently only transient. Recent data have shown that new targeted drugs (histone deacetylase and bromodomain and extra-terminal protein inhibitors) are promising, but their role has yet to be evaluated in NC. Centralized data review is necessary to improve our knowledge of paediatric NC. We propose a multimodal strategy based on published data and their personal experience.

Low dose epigallocatechin-3-gallate revives doxorubicin responsiveness by a redox-sensitive pathway in A549 lung adenocarcinoma cells.

Pulmonary cancer confronts the greatest hurdle of resistance against most chemotherapeutic drugs. This may be circumvented with a combination of conventional chemotherapy with bioactive herbal adjuvant. Epigallocatechin-3-gallate (EGCG), was investigated for its chemo-sensitizing property along with doxorubicin (Dox), in an intrinsically nonresponsive lung adenocarcinoma (LAC) cell line, A549. A compromised functionality of Dox was reversed when EGCG was used as an adjuvant. On one hand, Dox (10 μM)-EGCG (0.5 μM) post treatment combination decreased the drug efflux, multidrug-resistance (MDR) signaling, invasiveness while, on the other hand, it increased drug internalization, cell-cycle arrest, stress-induced damage, and finally cell death. The resistant nature of A549 was probably due to constitutive activation of nuclear erythroid 2-related factor 2 (Nrf2)and its upstream/downstream antioxidant effectors, which were also pro-oxidatively coordinated by EGCG. In conclusion low dose EGCG improved Dox-toxicity and imparted oxidative damage-mediated antineoplastic efficacy by reorienting the redox signaling in A549 LAC cells.

Brentuximab Vedotin in Combination with Nivolumab, Doxorubicin, and Dacarbazine in Newly Diagnosed Patients with Advanced Stage Hodgkin Lymphoma (SGN35-027, Trial in Progress)

Brentuximab Vedotin in Combination with Nivolumab, Doxorubicin, and Dacarbazine in Newly Diagnosed Patients with Advanced Stage Hodgkin Lymphoma (SGN35-027, Trial in Progress)

Selective Inhibition of Class II HDAC Isoforms 4 and 5 Provides a Promising Therapeutic Intervention for MLL-Rearranged Acute Lymphoblastic Leukemia in Infants

▪MLL-rearranged acute lymphoblastic leukemia (ALL) is characterized by deregulation of the epigenome and shows susceptibility towards epigenetic perturbators such as histone deacetylase (HDAC) inhibitors. Hence, HDACs represent attractive drug targets and a variety of small molecule HDAC inhibitors have been developed and evaluated for the treatment of hematological malignancies. However, most broad-spectrum inhibitors, which simultaneously target the majority of human HDAC isoforms, often induce toxicity, especially in combination with other therapeutic agents. Therefore, selective inhibition of only one or two HDAC isoforms may represent a better alternative, provided that disease-specific dependency on specific HDACs has been identified.We examined the effects of shRNA-mediated knock-down of the class II HDACs (i.e. HDAC4, HDAC5, HDAC6, HDAC7 and HDAC9) in the MLL-rearranged ALL cell lines SEM and ALL-PO. Except for HDAC9, loss of expression (both on the mRNA and protein level) of all HDACs led to strong reductions in viable cells (0.70 to 0.19-fold; p=0.02-0.0016) in both models due to apoptosis, cell cycle arrest, or a combination thereof.Next, we evaluated the in vitro efficacy of a variety of class II HDAC-specific inhibitors on a panel of MLL-rearranged ALL (n=5) using 4-day viability MTT assays. This revealed that the selective HDAC4/5 inhibitor LMK-235 was able to recapitulate the loss-of-function phenotype of HDAC4 and HDAC5. Dose response curves showed complete growth inhibition in MLL-rearranged ALL cell lines (n=5), as well as in primary MLL-rearranged infant ALL patient samples (n=4), with IC 50 values of ~100 nM and 40-100 nM, respectively. Importantly, at these concentrations, LMK-235 hardly affected whole bone marrow samples derived from healthy individuals (n=2), for which IC 50 values were ~1 µM.To further explore the potential of class II HDAC inhibitor-based therapeutic strategies, we performed a combinatorial drug screen to identify compounds that synergize with LMK-235. For this, a compound library (comprising >200 unique agents) was screened in the absence and presence of varying concentrations of LMK235 in the MLL-rearranged cell line models SEM and ALL-PO. This, and subsequent validation experiments in additional cell line models, revealed that Venetoclax (BCL2 inhibitor), Trametinib (MEK/ERK inhibitor), Ponatinib (multi-tyrosine kinase inhibitor) and Omipalisib (a PI3K/mTOR inhibitor) strongly synergized with LMK-235. Average ZIP synergy scores ranged from 10-30, with peak ZIP scores up to 40. Importantly, synergistic effects were consistent over all concentration combinations tested. The addition of 50-100 nM LMK-235 strongly reduced IC 50 values for Omipalisib, Ponatinib and Venetoclax (0.27-fold p=0.003, 0.11-fold p=0.0005, 0.75-fold p=0.0004, respectively) in both models.In preparation to assess the in vivo efficacy of LMK-235 in patient-derived xenograft (PDX) mouse models of MLL-rearranged infant ALL, pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed in immunodeficient NSG mice (n=5). For this, mice were treated with 20 mg/kg of LMK-235, daily administered via intraperitoneal injections for a total of 29 days. While none of the mice showed signs of toxicity or weight loss, LMK-235 plasma levels were stably maintained at concentrations that are highly effective against MLL-rearranged ALL cells in vitro.Taken together, these data demonstrate that various class II HDAC isoforms are targetable vulnerabilities in MLL-rearranged ALL and that pharmaceutical inhibition of HDAC4/5 by LMK-235 represents an attractive therapeutic option. Moreover, high levels of synergy observed between this HDAC inhibitor and various agents belonging to drug classes already reported to be effective against MLL-rearranged ALL, warrants pre-clinical evaluation in vivo. Currently, the assessment of the in vivo efficacy of LMK-235 monotherapy in MLL-rearranged infant ALL PDX models is in progress, after which promising synergistic HDAC inhibitor-based drug combinations will be evaluated. To determine the additional therapeutic value, the efficacy of LMK-235 and promising synergistic combinations will be evaluated in the background of conventional combination chemotherapy, where PDX models will receive a mouse-adapted version of induction therapy currently applied for treatment of MLL-rearranged infant ALL patients. DisclosuresNo relevant conflicts of interest to declare.

Emerging Immunotherapy for Acute Myeloid Leukemia.

Several immune checkpoint molecules and immune targets in leukemic cells have been investigated. Recent studies have suggested the potential clinical benefits of immuno-oncology (IO) therapy against acute myeloid leukemia (AML), especially targeting CD33, CD123, and CLL-1, as well as immune checkpoint inhibitors (e.g., anti-PD (programmed cell death)-1 and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) antibodies) with or without conventional chemotherapy. Early-phase clinical trials of chimeric antigen receptor (CAR)-T or natural killer (NK) cells for relapsed/refractory AML showed complete remission (CR) or marked reduction of marrow blasts in a few enrolled patients. Bi-/tri-specific antibodies (e.g., bispecific T-cell engager (BiTE) and dual-affinity retargeting (DART)) exhibited 11–67% CR rates with 13–78% risk of cytokine-releasing syndrome (CRS). Conventional chemotherapy in combination with anti-PD-1/anti-CTLA4 antibody for relapsed/refractory AML showed 10–36% CR rates with 7–24 month-long median survival. The current advantages of IO therapy in the field of AML are summarized herein. However, although cancer vaccination should be included in the concept of IO therapy, it is not mentioned in this review because of the paucity of relevant evidence.

Osteosarcoma of the hard palate in a dog ˗ case report

ABSTRACT The osteosarcoma (OSA) is the most diagnosed primary bone cancer in canine patients. This work reports a case of a canine, six years old, mongrel, female, intact, with an OSA in the hard palate. Physical examination detected a firm mass in the palate. Thoracic radiographs, hematological and biochemical exams, histopathological exams and computed tomography were requested. A chondroblastic OSA was diagnosed and the tumor was characterized by immunohistochemistry. There was never evidence of metastasis in this case. The treatment consisted of the combination of conventional chemotherapy, metronomic chemotherapy, and palliative care, aiming at greater survival and well-being of the patient since surgical excision was not possible due to the location and extension of the tumor. Osteogenic sarcomas of the hard palate are rarely seen and described in the literature. In this article we present a characterization of the osteosarcoma with uncommon localization in the hard palate.

Contrastive Studies of Cytarabine/Daunorubicin Dual-Loaded Liposomes Prepared by pH Gradient and Cu2+ Gradient Method.

Conventional combination chemotherapy often leads to unsatisfactory clinical outcomes due to the different distribution characteristics in vivo and the superimposed systemic toxicity of the drug cocktail. Co-encapsulated nano preparations have been gradually developed in recent years. In this work, cytarabine (Ara-C)/daunorubicin (DNR) liposomes were prepared by the pH gradient (ADL-pH) and Cu2+ gradient (ADL-Cu) methods. Ara-C did not show significant release from either ADL-Cu or ADL-pH in vitro during 168h, which related to its logPoct. Different drug-loading patterns showed different release characteristics of DNR due to the different existence forms, ADL-pH contains the citrate form, while in ADL-Cu, there is the Cu2+ complex. To evaluate the release behavior, daunorubicin liposome (DL) and daunorubicin-Cu2+ complex (DNR-Cu) were prepared. The addition of EDTA in the release medium significantly increased the release rate of DNR from DL-Cu, while lower pH accelerated DNR release from both DL-pH and DL-Cu. The PK confirmed that ADL-Cu and ADL-pH could prolong the drug circulation time, and ADL-Cu had a mean retention time 1.5 times that of ADL-pH. Furthermore, both liposomes allowed the two drugs to maintain a relatively constant plasma concentration ratio for a prolonged time. Cytotoxicity assays showed that Ara-C/DNR with a molar ratio of 5:1 and 3:1 exhibited an excellent synergistic effect, which was more obvious at 5:1. In vitro antitumor results revealed that ADL-Cu exhibited more cytotoxicity than ADL-pH. All factors tested in this work suggest the considerable potential of ADL-Cu and ADL-pH for anticancer treatment.

Elimination of dormant, autophagic ovarian cancer cells and xenografts through enhanced sensitivity to anaplastic lymphoma kinase inhibition.

Poor outcomes for patients with ovarian cancer relate to dormant, drug-resistant cancer cells that survive after primary surgery and chemotherapy. Ovarian cancer (OvCa) cells persist in poorly vascularized scars on the peritoneal surface and depend on autophagy to survive nutrient deprivation. The authors have sought drugs that target autophagic cancer cells selectively to eliminate residual disease. By using unbiased small-interfering RNA (siRNA) screens, the authors observed that knockdown of anaplastic lymphoma kinase (ALK) reduced the survival of autophagic OvCa cells. Small-molecule ALK inhibitors were evaluated for their selective toxicity against autophagic OvCa cell lines and xenografts. Autophagy was induced by reexpression of GTP-binding protein Di-Ras3 (DIRAS3) or serum starvation and was evaluated with Western blot analysis, fluorescence imaging, and transmission electron microscopy. Signaling pathways required for crizotinib-induced apoptosis of autophagic cells were explored with flow cytometric analysis, Western blot analysis, short-hairpin RNA knockdown of autophagic proteins, and small-molecule inhibitors of STAT3 and BCL-2. Induction of autophagy by reexpression of DIRAS3 or serum starvation in multiple OvCa cell lines significantly reduced the 50% inhibitory concentration of crizotinib and other ALK inhibitors. In 2 human OvCa xenograft models, the DIRAS3-expressing tumors treated with crizotinib had significantly decreased tumor burden and long-term survival in 67% to 79% of mice. Crizotinib treatment of autophagic cancer cells further enhanced autophagy and induced autophagy-mediated apoptosis by decreasing phosphorylated STAT3 and BCL-2 signaling. Crizotinib may eliminate dormant, autophagic, drug-resistant OvCa cells that remain after conventional cytoreductive surgery and combination chemotherapy. A clinical trial of ALK inhibitors as maintenance therapy after second-look operations should be seriously considered.

Brentuximab vedotin in combination with nivolumab, doxorubicin, and dacarbazine in newly diagnosed patients with advanced-stage Hodgkin lymphoma (Trial in Progress).

TPS8068 Background: Brentuximab vedotin (BV, ADCETRIS) is approved for the treatment of adults with treatment-naïve Stage III or IV cHL in combination with AVD (Connors 2017). Nivolumab is approved for treatment of adults with relapsed/refractory cHL. Both agents have been well tolerated with promising activity when combined with multi-agent chemotherapy. The combination of BV plus nivolumab was evaluated as a frontline treatment option for patients (pts) with cHL who are over 60 years and ineligible for or declined conventional combination chemotherapy (Friedberg, 2018). The ongoing study reported an ORR of 82% in 11 pts and appears well tolerated in this population. In another trial in 93 patients in the first salvage setting, the combination produced a 67% CR rate (Herrera 2018, Moskowitz 2019) and the majority of patients were able to undergo subsequent stem cell transplant. It is reasonable to expect that the combination of BV, nivolumab, A, and D (AN + AD) will result in high response rates and be well tolerated, with potentially less toxicity. Methods: SGN35-027 (NCT03646123) is a phase 2 study designed to evaluate the efficacy and safety of A+AVD when administered with growth factor prophylaxis in pts with stage III/IV cHL (Part A). Part B will evaluate the combination of AN + AD in a similar patient population. The primary objective of Part B is to estimate the CR rate at EOT in pts with treatment-naïve advanced cHL. Patients in Part B will have Ann Arbor Stage IIB/III/IV cHL or Stage IIA cHL with bulky mediastinal disease. Enrollment is ongoing in both parts of the study. Approximately 50 pts will be enrolled in Part B. All pts will be treated with BV 1.2 mg/kg, nivolumab 240 mg, doxorubicin 25 mg/m2, and dacarbazine 375 mg/m2, administered separately by IV infusion on Days 1 and 15 of each 28-day cycle for up to 6 cycles. Efficacy will be assessed by PET/CT scans at C2 and EOT. Disease assessments will be performed periodically during follow up. Disease response and progression will be assessed using Lugano with the incorporation of LYRIC (Cheson 2016). Clinical trial information: NCT03646123 .

SUMO pathway inhibition targets an aggressive pancreatic cancer subtype

ObjectivePancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however,...

Overexpression of annexin A5 might guide the gemtuzumab ozogamicin treatment choice in patients with pediatric acute myeloid leukemia

Background:Acute myeloid leukemia (AML) is a common hematological malignancy. Gemtuzumab ozogamicin (GO), a humanized anti-CD33 antibody conjugated with the potent anti-tumor antibiotic calicheamicin, represents a promising targeted therapy for AML. Annexin A5 (ANXA5) is a proposed marker for the clinical prognosis of AML to guide treatment choice.Methods:In total, 253 patients with pediatric AML were enrolled and divided into two treatment groups: conventional chemotherapy alone and conventional chemotherapy in combination with GO. Univariate, multivariate, and Kaplan–Meier survival analyses were conducted to assess risk factors and clinical outcomes, and to estimate hazard ratios (HRs) and their 95% confidence interval. The level of statistical significance was set at p < 0.05.Results:In the GO treatment group, high ANXA5 expression was considered a favorable prognostic factor for overall survival (OS) and event-free survival (EFS). Multivariate analysis showed that high ANXA5 expression was an independent favorable factor for OS (HR = 0.629, p = 0.084) and EFS (HR = 0.544, p = 0.024) distinct from the curative effect of GO treatment. When all patients were again divided into two groups, this time based on the median expression of ANXA5, patients undergoing chemotherapy combined with GO had significantly better OS (p = 0.0012) and EFS (p = 0.0003) in the ANXA5 high-expression group. Gene set enrichment analysis identified a relevant series of pathways associated with glutathione metabolism, leukocyte transendothelial migration, and hematopoietic cell lineage.Conclusion:The expression level of ANXA5 can help optimize the treatment regimen for individual patients, and patients with overexpression of ANXA5 may circumvent poor outcomes from chemotherapy combined with GO.

The Early Achievement of Measurable Residual Disease Negativity in the Treatment of Adults with Philadelphia-Negative B-Cell Acute Lymphoblastic Leukemia Is a Strong Predictor for Survival

The minimal or measurable residual disease (MRD) status following induction/consolidation chemotherapy is an important prognostic endpoint in adult patients with newly diagnosed acute lymphoblastic leukemia (ALL). However, the optimal time-point (TP) of MRD assessment and its impact on outcome remains unclear. We analyzed 215 patients with newly diagnosed Philadelphia negative B-cell ALL who received intensive chemotherapy, and had available MRD assessment by multicolor flow cytometry at two separate TPs. The median time to first TP (1TP) and second TP (2TP) were 24 and 110 days, respectively. At 1TP, 148 patients (68%) were MRD negative and 67 (32%) were positive. Of the 148 patients with negative MRD at 1TP, 147 (99%) maintained it through 2TP. Patients who were MRD negative at both TPs, early MRD responders, had the 3-year event-free survival (EFS), and overall survival (OS) rates of 65% and 76%, respectively. Patients with improved MRD status from positive to negative, late MRD responders, had lower 3-year EFS and OS rates, 42% and 58%, respectively (P = .001). Multivariate analysis showed that KMT2A (MLL) rearrangement and MRD positivity at 1TP were the only factors correlated with worse OS. In conclusion, the earlier achievement of MRD negative remission is a stronger prognostic factor for survival.