Need For Better Therapeutic Options Research Articles

A qualitative evaluation of the oncologists’, neurologists’, and pain specialists’ views on the management and care of chemotherapy-induced peripheral neuropathy in The Netherlands

PurposeIn treating cancer, different chemotherapy regimens cause chemotherapy-induced peripheral neuropathy (CIPN). Despite recent international guidelines, a gold standard for diagnosis, treatment, and care is lacking. To identify the current clinical practice and the physicians’ point of view and ideas for improvement, we evaluated CIPN care by interviewing different specialists involved.MethodsWe performed semi-structured, audio-recorded, transcribed, and coded interviews with a purposive sample of oncologists, pain specialists, and neurologists involved in CIPN patients’ care. Data is analyzed by a constant comparative method for content analysis, using ATLAS.ti software. Codes, categories, and themes are extracted, generating common denominators and conclusions.ResultsWith oncologists, pain specialists, and neurologists, nine, nine, and eight interviews were taken respectively (including three, two, and two interviews after thematic saturation occurred). While useful preventive measures and predictors are lacking, patient education (e.g., on symptoms and timely reporting) is deemed pivotal, as is low-threshold screening (e.g., anamnesis and questionnaires). Diagnosis focusses on a temporal relationship to chemotherapy, with adjuvant testing (e.g., EMG) used in severe or atypical cases. Symptomatic antineuropathic and topical medication are often prescribed, but personalized and multidimensional care based on individual symptoms and preferences is highly valued. The limited efficacy of existing treatments, and the lack of standardized protocols, interdisciplinary coordination, and awareness among healthcare providers pose significant challenges.ConclusionBesides the obvious need for better therapeutic options, and multidisciplinary exploration of patients’ perspectives, a structured and collaborative approach towards diagnosis, treatment, referral, and follow-up, nurtured by improving knowledge and use of existing CIPN guidelines, could enhance care.

The potential of PARP as a therapeutic target across pediatric solid malignancies

BackgroundPediatric cancer is the leading cause of disease-related death in children and the need for better therapeutic options remains urgent. Due to the limited number of patients, target and drug development for pediatrics is often supplemented by data from studies focused on adult cancers. Recent evidence shows that pediatric cancers possess different vulnerabilities that should be explored independently from adult cancers.MethodsUsing the publicly available Genomics of Drug Sensitivity in Cancer database, we explore therapeutic targets and biomarkers specific to the pediatric solid malignancies Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma, and rhabdomyosarcoma. Results are validated using cell viability assays and high-throughput drug screens are used to identify synergistic combinations.ResultsUsing published drug screening data, PARP is identified as a drug target of interest across multiple different pediatric malignancies. We validate these findings, and we show that efficacy can be improved when combined with conventional chemotherapeutics, namely topoisomerase inhibitors. Additionally, using gene set enrichment analysis, we identify ribosome biogenesis as a potential biomarker for PARP inhibition in pediatric cancer cell lines.ConclusionCollectively, our results provide evidence to support the further development of PARP inhibition and the combination with TOP1 inhibition as a therapeutic approach in solid pediatric malignancies. Additionally, we propose ribosome biogenesis as a component to PARP inhibitor sensitivity that should be further investigated to help maximize the potential utility of PARP inhibition and combinations across pediatric solid malignancies.

Recent therapeutic approaches to cystathionine beta-synthase-deficient homocystinuria.

Cystathionine beta-synthase (CBS)-deficient homocystinuria (HCU) is the most common inborn error of sulfur amino acid metabolism. The pyridoxine non-responsive form of the disease manifests itself by massively increasing plasma and tissue concentrations of homocysteine, a toxic intermediate of methionine metabolism that is thought to be the major cause of clinical complications including skeletal deformities, connective tissue defects, thromboembolism and cognitive impairment. The current standard of care involves significant dietary interventions that, despite being effective, often adversely affect quality of life of HCU patients, leading to poor adherence to therapy and inadequate biochemical control with clinical complications. In recent years, the unmet need for better therapeutic options has resulted in development of novel enzyme and gene therapies and exploration of pharmacological approaches to rescue CBS folding defects caused by missense pathogenic mutations. Here, we review scientific evidence and current state of affairs in development of recent approaches to treat HCU.

EXTH-07. AN ANTISENSE OLIGONUCLEOTIDE AGAINST TUMOR MICROTUBES IN GLIOBLASTOMA AS A NEW THERAPEUTIC OPTION TO IMPROVE TUMOR SPECIFIC THERAPY

Abstract Glioblastomas are known to be highly therapy resistant tumors. The description of tumor microtubes (TMs) as long cellular protrusions that connect glioblastoma cells to a network resistant against all standard therapies advanced the basic biological understanding of the disease and offers a new therapeutic target. An antisense oligonucleotide (ASO) against the production of a protein involved in formation and function of TMs was developed and tested in a xenograft mouse model of human glioblastoma cells. After the implantation of fluorescent tumor cells under a chronic cranial window and the establishment of the tumor, the ASO treatment was started with a continuous micropump application directly into the central nervous system (CNS) and treatment effects were observed in a two-photon microscope. Furthermore, co-treatment with irradiation was tested and tumor size as well as protein expression evaluated in and ex vivo. This led to the conclusion that the setup of combined continuous pump application and two photon microscopy is technically feasible and tolerable. It offers the possibility of applying compounds directly into the CNS under live and longitudinal readouts. The fluorescently tagged ASO was traced in the brain parenchyma over weeks proving a high stability of the compound. In combination with radiotherapy, animals treated with the active ASO against the protein of formation and function of TMs showed a smaller tumor size than animals treated with radiotherapy and the non-targeting ASO. The targeted protein was expressed less in the treated animals then the animals receiving the control ASO and the extend of protein expression correlated with tumor size. Hence, after successful therapies with ASOs in other neurologic diseases and the need for better therapeutic options for glioblastoma patients, the development of an ASO against a protein involved in the TM formation and function offers a new therapeutic option with high translational potential.

ATRT-22. Outcomes for children with recurrent atypical teratoid rhabdoid tumor: A single institution study with updated molecular and germline analysis

BACKGROUND: Children with recurrent atypical teratoid rhabdoid tumor (recATRT) who fail frontline therapies have dismal outcomes. The association of ATRT molecular groups (SHH, TYR and MYC) and presence of underlying cancer predisposition with survival post-recurrence (postRD) is unknown. METHODS: We previously reported outcomes from a single-institution retrospective study of children <21 years with recATRT treated at St. Jude Children’s Research Hospital from 2000 to 2020. Herein we report updated progression-free survival (PFS2: time from initial recurrence to subsequent first progression) and overall survival (OSpostRD: time from initial recurrence to death/last follow-up) outcomes by molecular groups determined by tumor DNA methylation and by germline SMARCB1/SMARCA4 alterations (GLA). RESULTS: Median age and time from initial diagnosis to recurrence for 64 eligible patients were 2.1 years (range: 0.5-17.9 years) and 5.4 months (range: 0.5–125.6 months), respectively. The 2- and 5-year PFS2 and OSpostRD were 3.1% (±1.8%)/1.6% (±1.1%) and 20.3% (±4.8%)/7.9% (±3.8%), respectively. PFS2 did not differ by molecular groups (p=0.210) for 42 participants with available data (MYC=11, SHH=21, TYR=10). Children with TYR group had a better 2-year OSpostRD [60.0% ±14.3% (TYR) vs. 18.2% ±9.5% (MYC) or 4.8% ±3.3% (SHH)] (p=0.018). In univariate analyses, OSpostRD was also better with older age at diagnosis (≥ 1 year vs <1 year; p=0.03), female gender (p=0.008), and metastatic site of recurrence compared to local or combined sites of disease (p<0.001). OSpostRD did not differ for those with positive GLA (n=12) compared to those without (n=21) (p=0.231). Only 6 children (9.4%) (TYR=4, SHH=1, NA=1) were alive at median follow-up of 7.7 years from recurrence. CONCLUSION: Children with recATRT have extremely poor outcomes. Older age at diagnosis, female gender, TYR group, and metastatic site of initial recurrence were associated with longer survival in our study. These results reinforce the dire need for better therapeutic options.

Abstract 4034: High throughput synergy screening identifies therapeutic combinations for Merkel cell carcinoma

Abstract Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer. MCC is virus-positive (VP-MCC) in the majority of cases wherein Merkel cell polyomavirus is integrated into the host genome. The remainder of cases are virus-negative (VN-MCC) and are associated with mutations induced by ultraviolet light. Primary MCC is effectively treated by surgical resection and radiotherapy, but for metastatic MCC, outcomes for conventional chemotherapy are poor. Immune checkpoint inhibitors are more likely to produce durable responses in metastatic MCC, but they are not effective in all cases and are not a viable option for patients with immunosuppression. To address the need for better therapeutic options, we utilized high-throughput small molecule screening to assess the efficacy of ~4,000 drugs in reducing VP-MCC and VN-MCC viability. Among the compounds we screened, navitoclax was identified as an effective agent against VP-MCC cell lines, compared to VN-MCC or control cells. However, navitoclax clinical application is limited by dose-dependent thrombocytopenia. One strategy to reduce thrombocytopenia risk is to combine a lower dose of navitoclax with another MCC-effective agent. To identify effective drug combinations, we performed a synergy screen with 1912 pairings of navitoclax with each of the clinically relevant compounds in the NCATS Mechanism Interrogation PlatE (MIPE). We were able to identify synergy between navitoclax and multiple drug classes. High priority drug combinations are now being evaluated for toxicity and efficacy in pre-clinical xenograft models of MCC. Our study has identified novel therapeutic combinations for the treatment of VP-MCC. By focusing on drugs already in clinical use, validated combinations will be quickly available to patients for whom immunotherapy is not available or effective. Citation Format: Khalid Garman, Tara Gelb, Daniel Urban, Matthew Hall, Isaac Brownell. High throughput synergy screening identifies therapeutic combinations for Merkel cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4034.

Long-chain fatty acid oxidation disorders: managed care and specialty pharmacy implications

Long-chain fatty acid oxidation disorders (LC-FAODs) represent a group of rare inborn errors of metabolism characterized by acute crises of energy metabolism and severe energy deficiency. Clinical manifestations include rhabdomyolysis, liver dysfunction, severe hypoglycemia, and cardiomyopathy. The symptoms associated with these genetic disorders may result in frequent hospitalizations and early death. Many patients with LC-FAODs experience major clinical events and significant morbidity and mortality that portends a substantial need for better therapeutic options for these disorders. Triheptanoin was recently approved for the treatment of LC-FAODs. As with any novel agent for rare diseases, the treatment adoption and coverage criteria for rare disease therapy such as this presents challenges for managed care decision makers. Both managed care decision makers and specialty pharmacists must ensure that healthcare professionals provide appropriate patient and caregiver education surrounding the management of LC-FAODs, including vital information on adopting emerging agents into the therapy armamentarium for these disorders.

Management of glioblastoma: State of the art and future directions.

Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There is a slight predominance in males, and incidence increases with age. The standard approach to therapy in the newly diagnosed setting includes surgery followed by concurrent radiotherapy with temozolomide and further adjuvant temozolomide. Tumor-treating fields, delivering low-intensity alternating electric fields, can also be given concurrently with adjuvant temozolomide. At recurrence, there is no standard of care; however, surgery, radiotherapy, and systemic therapy with chemotherapy or bevacizumab are all potential options, depending on the patient's circumstances. Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management. The recently revised classification of glioblastoma based on molecular profiling, notably isocitrate dehydrogenase (IDH) mutation status, is a result of enhanced understanding of the underlying pathogenesis of disease. There is a clear need for better therapeutic options, and there have been substantial efforts exploring immunotherapy and precision oncology approaches. In contrast to other solid tumors, however, biological factors, such as the blood-brain barrier and the unique tumor and immune microenvironment, represent significant challenges in the development of novel therapies. Innovative clinical trial designs with biomarker-enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma.

Phase II study of pembrolizumab plus SurVaxM for glioblastoma at first recurrence.

TPS2581 Background: Glioblastoma is the most common primary malignant brain tumor with median survival of approximately 15-16 months. Following first recurrence, progression free survival at six months ~15%. There is no therapy in recurrent glioblastoma associated with any survival benefit and there is an urgent need for better therapeutic options. Immunotherapy is one promising option for patients with cancer. This is being explored in glioblastoma and a number of forms of active specific vaccination and immune checkpoint based approaches have been devised and are being investigated in glioblastoma. Methods: Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor. Survivin is a 16.5 kDa intracellular protein that belongs to the inhibitor of apoptosis protein (IAP) family. SurVaxM is a 15 amino acid antigenic peptide that targets surviving capable of binding several human MHC class I molecules. Primary Objective is to assess clinical activity of Pembrolizumab and SurVaxM in patients with recurrent glioblastoma using progression free survival at 6 months (PFS-6) as determined using RANO criteria. Secondary Objective(s) includes safety and tolerability of combination, response rates, progression free survival and overall survival. Exploratory Objective include measuring cellular and humoral immune responses during concurrent administration of Pembrolizumab and SurVaxM. This is a phase II study of two arms in patients with recurrent glioblastoma. Arm A is patients with first recurrence of glioblastoma who have failed prior chemotherapy and radiation but have not received any immunotherapy. Arm B is an exploratory arm of glioblastoma patients who have failed prior anti-PD1 therapy. This clinical trial will enroll 41 patients with glioblastoma at first recurrence (bevacizumab naïve) in arm 1.This will include a 6-patient toxicity/safety run-in. There will an exploratory cohort of 10 patients who have failed prior PD1 blockade for a total of 51 patients in 2 arms. Key inclusion criteria include diagnosis of glioblastoma, Age ≥18 years old, Previous first line treatment with at least radiotherapy with or without temozolomide and Documented first recurrence of GBM and Karnofsky performance status of 70 and normal organ function. Key exclusion criteria include more than one recurrence of GBM, presence of extracranial metastatic or leptomeningeal disease, patients with &gt; 1 cm midline shift on imaging. Patients must not require &gt; 10 mg daily of prednisone equivalent. Clinical trial information: NCT04013672 .

Limited Stage Small Cell Bladder Cancer: Outcomes of a Contemporary Cohort

BACKGROUND: Limited stage small cell bladder cancer is curable with multi-modality therapy using external beam radiotherapy or radical cystectomy. The optimal management strategy for this rare disease is still debated, yet few case series have described patients treated after 2010. OBJECTIVE: To analyze outcomes from a contemporary cohort of patients undergoing definitive treatment. METHODS: Patients diagnosed with small cell bladder cancer after January 1, 2010 were identified from an institutional database. Clinical histories were collected by chart review. Survival outcomes were analyzed in patients who received curative-intent therapy consisting of bladder radiotherapy or cystectomy. RESULTS: Thirty patients with limited stage disease that received definitive therapy were identified. Seventeen patients received primary radiotherapy, and thirteen underwent cystectomy. Median age was 70 years. Median follow up was 39.6 months (range 7.2–95.8). The median overall survival of patients undergoing radiotherapy or cystectomy were 36.8 and 30.6 months, respectively (hazard ratio 0.99, 95% confidence interval 0.35–2.85). The median metastasis free survival for patients receiving radiotherapy was not reached, and 18.9 months in the cystectomy group (hazard ratio 0.94, 95% confidence interval 0.34–2.61). The most common sites of relapse were lymph node (n = 6) and bone (n = 5). Brain metastases were less common (n = 3). CONCLUSIONS: Patients receiving cystectomy or radiotherapy had similar outcomes in this contemporary series, but definitive comparisons are limited by the cohort size and high censoring rate (53%). Survival in our cohort is improved compared with older reports, though outcomes remain poor, reiterating the need for better therapeutic options.

A phase II trial of nintedanib in recurrent malignant pleural mesothelioma (MPM).

e20061 Background: Malignant pleural mesothelioma (MPM) is a disease that is resistant to chemotherapy and there remains an unmet need for better therapeutic options. Nintedanib (BIBF 1120) is an oral multikinase inhibitor impacting VEGFR, FGFR, PDGFR, and other kinase activity such as TGFß signaling pathways. VEGF, FGF, and TGFβ are commonly expressed in MPM. We conducted a phase II trial in patients with recurrent MPM after platinum-based chemotherapy. Methods: Patients (pts) with MPM previously treated with platinum-based chemotherapy, performance status (PS) 0-1, adequate organ function, and no contraindications to anti-angiogenic therapy were eligible for treatment. Nintedanib 200 mg twice per day was administered until disease progression or unacceptable toxicity. The primary endpoint was the 4-month progression-free survival (PFS). A two-stage design was used and &gt; 4 pts had to have a PFS of ≥4 months to proceed to the second stage. Results: Twenty pts. were enrolled. The median age was 70 yrs. (32-81), 90% were male, and 80% were PS = 1. The histology was 70% epithelioidal, 5% sarcomatoid, 10% biphasic, and 15% unknown. 15% had prior bevacizumab. The median follow-up is 16.4 mo. A median of 2 treatment cycles (range 1-18) were delivered. There were no responses but 40% had stable disease. The median PFS was 1.8 mo. (95% CI: 1.68, 3.55) and the PFS rate at 4 mo. was 13%. The median OS was 4.2 mo. (95% CI: 2.53, 8.74) and the OS rate at 4 mo. was 55%. Toxicities were usually grade 1-2 and included diarrhea, fatigue, edema, transaminase elevation, anorexia, nausea, vomiting and dyspnea. Conclusions: The activity of nintedanib in previously treated MPM pts. was modest. The trial did not meet the primary PFS endpoint. However, there was a small subset of pts. that had prolonged stable disease for &gt; 4 months thus potentially deriving some clinical benefit from treatment. Supported by Boehringer Ingelheim. Clinical trial information: NCT02568449.

Real-world outcomes in patients with unresected stage III non-small cell lung cancer

This study examined real-world clinical outcomes such as progression-free survival (PFS), time to metastasis (TTM), overall survival (OS), and health-related quality of life (HRQOL) in patients with unresected stage III non-small cell lung cancer (NSCLC) treated in the community setting. A retrospective review of medical records extracted from 10 US community oncology practices was conducted. Eligible patients were adults diagnosed with stage III NSCLC from 1/1/2011 to 3/1/2016 without evidence of surgical resection within 6 months after stage III NSCLC diagnosis (index date). PFS, OS, and TTM were assessed from the index date, and were analyzed using Kaplan–Meier and Cox regression analyses. HRQOL was assessed for a subset of patients using a patient-reported measure, the 86-item Patient Care Monitor (PCM). Linear mixed models (LMM) were used to assess the impact of patient characteristics and change in PCM scores associated with progression. Among the sample of 478 patients, median PFS (95% confidence interval) was 10 months (9–11), median OS was 20 months (17–22), and median TTM was 30 months (23–45). Most patients (58.2%) experienced disease progression, which the LMM showed to be associated with significant worsening of physical symptoms and psychological states (p < 0.001). This study documented PFS and OS consistent with published literature. The majority of patients experienced disease progression, which was associated with worsening of HRQOL. These findings highlighted the need for better therapeutic options in patients with unresected stage III NSCLC with potential to improve patient outcomes and HRQOL.

Randomized control trial comparing quality of life of patients with end-stage peritoneal metastasis treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC) and intravenous chemotherapy.

BackgroundPeritoneal metastasis (PM) is a common occurrence in gynaecological and gastrointestinal cancers and is associated with poor survival. Patients typically present with ascites, abdominal pain, malnutrition, nausea, emesis, and bowel obstruction which significantly compromise the quality of life (QoL). The treatment remains a particular challenge, with palliative systemic chemotherapy being the standard of care. However, the efficacy of systemic chemotherapy is poor but with high potential for side effects and complications. QoL plays an important role in patients with PM and is deteriorating continuously until death. Thus, there is an obvious medical need for better therapeutic options in PM for prolonging survival and preserving QoL by reducing both disease-related symptoms and therapy side effects. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique for delivering pressurized normothermic chemotherapy into the abdominal cavity as an aerosol. This concept seems to enhance the effectiveness of intraperitoneal chemotherapy by taking advantage of the physical properties of gas and pressure by generating an artificial pressure gradient and enhancing tissue uptake and distributing drugs homogeneously within the closed and expanded peritoneal cavity.MethodsThe primary objective of this study is to assess QoL and symptoms in a consecutive cohort of patients with PM treated with PIPAC procedure in comparison with conventional systemic intravenous chemotherapy. QoL is assessed prospectively using European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30(Version 3.0) questionnaire. QLQ-C30 is a 30-question self-administered questionnaire inquiring about global health status, 9 individual symptoms, and 5 functional scales. Baseline QoL is measured using the global physical health functional score, and symptom scores derived from EORTC QLQ30 questionnaire before starting therapy, followed by at 60, 120, and 180 days after the first intervention. Calculated sample size is 119 and rounded to 120. For each treatment group, sample size of 60 will be enrolled; Intervention model: IV chemotherapy group (control group) and PIPAC group (experimental group); Study type: prospective randomized control intervention trialDiscussionAll consecutive patients diagnosed with advanced end-stage PM are randomized to be treated with PIPAC or IV chemotherapy. The primary objective of this study is to determine the QoL after three cycles of PIPAC in comparison with six cycles of systemic chemotherapy. The secondary outcome measures include morbidity and mortality. Analysis is by intention to treat.ResultsThe effect of systemic chemotherapy remains limited on the peritoneum due to poor vascularization and low penetration. Side effects after systemic chemotherapy for PM are relatively frequent. QoL plays an important role in these patients and is deteriorating continuously due to the disease or therapy related. Thus, there is need for better therapeutic options for prolonging survival and preserving QoL by reducing both disease-related symptoms and therapy side effects. PIPAC is a novel minimally invasive repeatable treatment modality which demonstrated potentially encouraging tumour response and only minimal toxicity in patients with PM of various origins. It can optimize local drug delivery and improve clinical outcome due to superior pharmacological properties as compared to systemic chemotherapy.Trial registrationREF/2018/08/021225 Registered on Clinical Trials Registry-India (CTRI); www.ctri.nic.in

Survival differences among patients with hepatocellular carcinoma based on the stage of disease and therapy received: pre and post sorafenib era.

The incidence of hepatocellular carcinoma (HCC) is increasing. Development of newer therapeutic modalities has changed the paradigm of HCC treatment in recent years. So, the aim of our study is to analyze the impact of these treatment modalities into the survival of HCC patients, based on the stage of HCC in real life practice. We analyzed the data from the SEER database: Incidence - SEER 18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2015 Sub (1973-2013 varying). Relative survival rates (RSRs) and hazard ratios (HRs) were measured for patients diagnosed with HCC between 2001 and 2013. Rates were compared between pre sorafenib [2001-2007] and post sorafenib [2008-2013] eras. A total of 50,088 patients (21,435 in pre sorafenib era and 28,653 in the post-sorafenib era) were included with HCC from SEER database. The median relative survival for the entire population was 14 months with 5-year RSR of 21.20%; 11 months for those diagnosed in 2001-2007 with 5-year RSR 19.30% and 17 months for those diagnosed in 2008-2013 with 5-year RSR 22.40% (P<0.01). This survival improvement was largely limited to HCC patients with single nodule (5-year RSR; 35.1% vs. 37.00% for pre and post sorafenib era respectively; P value <0.01) and multiple nodules without vascular invasion (5-year RSR; 19.90% vs. 22.60% for pre and post sorafenib era respectively; P value <0.01). RSR remained extremely poor with no significant improvement for advanced stage HCC who had vascular invasion (P=0.37) or distant metastasis (P=0.10), respectively for pre and post sorafenib era in each category. Survival improved since 2008, for HCC patients who received either no surgical intervention (P<0.01) or received tumor-directed therapy (P<0.01), however, it remained significantly poor compared to the patients who received lobectomy or hepatectomy and transplant. Approximately 70% of patients from our study population did not receive any HCC directed surgical intervention and among this, more than 40% of patients were with single nodule in the liver. Survival in patients with HCC has improved since 2008, which is limited to early stage HCC. Survival of advanced stage HCC patients is extremely poor and has not shown any significant improvement since the approval of sorafenib, emphasizing the need for better therapeutic options. Not receiving any surgical intervention is associated with significantly poor prognosis. Large numbers of early stage HCC patients were not able to receive surgical interventions. This can impose a significant financial burden, as these patients would progress on to the advanced stage, where treatment options are very limited and not as cost-effective. This emphasizes the need for further research to identify various barriers and the possible need for healthcare policy changes.

A novel compound which sensitizes BRAF wild-type melanoma cells to vemurafenib in a TRIM16-dependent manner

There is an urgent need for better therapeutic options for advanced melanoma patients, particularly those without the BRAFV600E/K mutation. In melanoma cells, loss of TRIM16 expression is a marker of cell migration and metastasis, while the BRAF inhibitor, vemurafenib, induces melanoma cell growth arrest in a TRIM16-dependent manner. Here we identify a novel small molecule compound which sensitized BRAF wild-type melanoma cells to vemurafenib. High throughput, cell-based, chemical library screening identified a compound (C012) which significantly reduced melanoma cell viability, with limited toxicity for normal human fibroblasts. When combined with the BRAFV600E/K inhibitor, vemurafenib, C012 synergistically increased vemurafenib potency in 5 BRAFWT and 4 out of 5 BRAFV600E human melanoma cell lines (Combination Index: CI < 1), and, dramatically reduced colony forming ability. In addition, this drug combination was significantly anti-tumorigenic in vivo in a melanoma xenograft mouse model. The combination of vemurafenib and C012 markedly increased expression of TRIM16 protein, and knockdown of TRIM16 significantly reduced the growth inhibitory effects of the vemurafenib and C012 combination. These findings suggest that the combination of C012 and vemurafenib may have therapeutic potential for the treatment of melanoma, and, that reactivation of TRIM16 may be an effective strategy for patients with this disease.

TRX-E-002-1 Induces c-Jun-Dependent Apoptosis in Ovarian Cancer Stem Cells and Prevents Recurrence In Vivo.

Chemoresistance is a major hurdle in the management of patients with epithelial ovarian cancer and is responsible for its high mortality. Studies have shown that chemoresistance is due to the presence of a subgroup of cancer cells with stemness properties and a high capacity for tumor repair. We have developed a library of super-benzopyran analogues to generate potent compounds that can induce cell death in chemoresistant cancer stem cells. TRX-E-002-1 is identified as the most potent analogue and can induce cell death in all chemoresistant CD44(+)/MyD88(+) ovarian cancer stem cells tested (IC50 = 50 nmol/L). TRX-E-002-1 is also potent against spheroid cultures formed from cancer stem cells, chemosensitive CD44(-)/MyD88(-) ovarian cancer cells, and heterogeneous cultures of ovarian cancer cells. Cell death was associated with the phosphorylation and increased levels of c-Jun and induction of caspases. In vivo, TRX-E-002-1 given as daily intraperitoneal monotherapy at 100 mg/kg significantly decreased intraperitoneal tumor burden compared with vehicle control. When given in combination with cisplatin, animals receiving the combination of cisplatin and TRX-E-002-1 showed decreased tumor burden compared with each monotherapy. Finally, TRX-E-002-1 given as maintenance treatment after paclitaxel significantly delayed disease recurrence. Our results suggest that TRX-E-002-1 may fill the current need for better therapeutic options in the control and management of recurrent ovarian cancer and may help improve patient survival. Mol Cancer Ther; 15(6); 1279-90. ©2016 AACR.

Histone Modifications as Molecular Targets in Nasopharyngeal Cancer.

Nasopharyngeal carcinoma (NPC) is a cancer of the nasopharyngeal epithelium with distinct geographical, ethnic and racial distribution. Several genetic, ethnic and environmental risk factors, have been implicated in nasopharyngeal pathogenesis and of significance, is the Epstein - Barr virus (EBV)- latent infection observed in most patients. Patients with NPC are typically diagnosed only in advanced stages due to non-specific symptoms, and hence, they respond poorly to therapy. Currently, low survival rates, severe complications, tumour metastasis and recurrence following chemo-radiotherapy, delineate the need for better therapeutic options to combat the disease. Recent studies have shown that epigenetic mechanisms such as DNA methylation, histone modifications and microRNAs, which are altered in the EBV genome as well as in the host cells, may underlie the initiation and progression of NPC. Histone acetylation and deacetylation which are mediated by enzymes, namely histone acetyl transferases (HATs) and histone deacetylases (HDACs), are known to regulate gene expression and several cellular processes. HDACs are also involved in maintaining the EBV latent cycle and thus, HDAC inhibitors (HDACi) are potent inducers of EBV reactivation, which is critical for the expression of the lytic proteins, thereby providing novel targets for therapy, as well as mediating enhanced killing of cancer cells, when used alone or along with additional anti-cancer agents in EBV associated malignancies. Recently, three FDA- approved HDACi have been used for the treatment of T-cell lymphoma, while several others are in clinical trials, making histone modifications excellent candidates for targeted therapy. In this review, we summarize the epigenetic mechanisms altered in NPC, with a focus on histone modifications for targeted therapy.

Gout: Update on Current Therapeutics

Gout is the most common inflammatory arthritis in adults. Given the increasing prevalence of gout and associated comorbidities, there is a growing need for better therapeutic options. While current treatment options satisfactorily control the disease in some patients, many patients, especially those with associated comorbidities, have contraindications to current treatments and need more treatment options. New drugs are needed to further improve our treatment, especially in patients with associated comorbidities. The duration of therapy for acute and chronic gout as well as combination of therapies, recommended by the American College of Rheumatology (ACR) guidelines, need to be further studied. The past decade has been an exciting time for gout research with significant advances in our understanding of disease pathogenesis and its treatment. The new ACR guidelines have improved gout visibility and will improve gout awareness and treatment in the future. With growing treatment options, gout is becoming a disease that can be cured.

Reported side effects, bother, satisfaction, and adherence in patients taking hydrocodone for non-cancer pain

Pain is a prevalent condition that often involves a neuropathic component. Hydrocodone is one of the most widely used opioids for pain but is often associated with side effects (SEs). This study sought to characterize the experience of patients taking hydrocodone for non-cancer pain. A nationwide survey of adults in the United States taking hydrocodone for non-cancer pain was conducted. The survey included questions to characterize these patients and their experience with hydrocodone-related SEs. A neuropathic pain subgroup also was examined. Among 630 respondents, the average age was 50.1 years (14.25). Most (90.6 percent) were Caucasian and 72.5 percent were female. Back pain or low back pain was the most common (42.1 percent) type of pain. Almost three-fourths (73.3 percent) experienced at least one SE, and 67.3 percent reported being bothered. More than three-fourths (78.3 percent) reported being satisfied with hydrocodone relieving pain; however, less (74.8 percent) reported being satisfied with it overall. More than one-fourth (27.6 percent) reported taking hydrocodone less than instructed with 41.4 percent of them reporting that SEs were bothersome as a reason. A greater percent of the neuropathic pain subgroup (266 respondents) experienced at least one SE (80.8 percent) and were bothered by them (75.6 percent). Overall satisfaction was slightly lower (71.1 percent) among these respondents, and among the 24.8 percent taking less than instructed, more than half (54.5 percent) reported that SEs were bothersome as a reason. This study demonstrates an unmet need for better therapeutic options to manage pain, including neuropathic pain. Therapies that offer improved tolerability also may increase adherence, which could affect overall satisfaction and response to pain management.

Thymidylate Synthase Inhibition with the Novel Fluoropyrimidine FdUMP[10] Is Highly Effective Against Acute Lymphoblastic Leukemia

AbstractAbstract 1505Despite significant improvements in cure rates in pediatric patients, outcomes in adults with acute lymphoblastic leukemia (ALL) remain dismal with an estimated 5-year survival of less than 10% for patients over the age of 60. Compared to children, ALL in adults is characterized by an increased incidence of poor prognostic cytogenetics, lower complete remission rates, and higher relapse rates. Once relapse occurs in adults, the outcome is truly dismal, with a 6% salvage rate with current therapies. Initial treatment of ALL combines essentially all currently used agents, leaving very few therapies once relapse occurs. There is a clear need for better therapeutic options for these patients.5-Fluorouracil (5-FU) is a fluoropyrimidine (FP) prodrug that must first be converted to 5-fluoro-2’-deoxyuridine-5’-O-monophosphate (FdUMP) in order to inhibit thymidylate synthase (TS) and shut down tumor thymidine synthesis. It can also be metabolized to a ribose metabolite that interferes with RNA processing and leads to toxicity in any transcriptionally active cell. The profound GI toxicities of 5-FU and lack of potency against ALL has lead to the abandonment of TS inhibition in the treatment of ALL. In contrast, FdUMP[10] is a oligodeoxynucleotide containing 10 FdUMP moieties linked by phosphodiester bonds. FdUMP[10] has profound activity against preclinical models of acute myeloid leukemia (AML), with minimal toxicities. The human T cell ALL cell line, Jurkat, was extremely sensitive to FdUMP[10], with an IC50of 5.4nM (95% CI 4.609–6.417). We sought to determine the activity of FdUMP[10] against additional preclinical ALL models.In vitro, FdUMP[10] exhibited remarkable activity against the human T and B Cell ALL cell lines, DG75, Molt-4, CCRF-CEM, and SUP-B15 with an average IC50 value of 1.83nM (Range 0.21–4.1nM). In two murine ALL cell lines driven by expression of BCR-ABL, FdUMP[10] exhibited even greater activity, with an average IC50 value of 0.662nM (range 0.125–1.2nM). For comparison we also tested 5-FU and cytarabine in the same assay against DG75, MOLT-4 and a BCR-ABL driven murine line. In all cases FdUMP[10] was the most potent agent and was more than 1000 times more potent than 5-FU despite having only 10 times the FP content. In vivo, FdUMP[10] treatment provided a statistically significant increase in survival in a BCR-ABL driven, syngeneic ALL mouse model (p=0.0002 by log rank test). In a separately derived syngeneic model expressing the T315I variant of BCR-ABL, treatment with FdUMP[10] significantly prolonged survival (p=0.0013).In AML models exposure to FdUMP[10] resulted in apoptosis. To assess if ALL cells undergo a similar apoptotic response we exposed human and mouse ALL cells to FdUMP[10] and assessed for apoptosis induction via propidium iodide (PI) and Annexin V staining. As we found previously in AML models, FdUMP[10] exposure resulted in a robust induction of Annexin V and PI staining consistent with an apoptotic response. The level of apoptosis with FdUMP[10] could not be reproduced by 5-FU even when used at 100 times higher concentration.To determine the effect of FdUMP[10] on thymidylate synthase (TS) activity in ALL, Jurkat cells were exposed to 10nM FdUMP[10] or 100nM 5- FU and TS activity was assayed. We found a profound and prolonged inhibition with FdUMP[10] compared to 5-FU, despite the identical amount of fluoropyrimidine.FdUMP[10] is synergistic with doxorubicin and cytarabine in AML models. To assess whether FdUMP[10] could synergize with targeted therapy in ALL, Baf-3 cells expressing BCR-ABL were exposed to the tyrosine kinase inhibitor nilotinib plus FdUMP[10]. The combination was synergistic, with combinatory index values of 0.7113 to 0.4803. In preliminary data in vivo, the combination of FdUMP[10] and nilotinib resulted in a greater reduction in leukemic burden then nilotinib alone.In summary, FdUMP[10] exhibited remarkable activity against human and murine ALL cells in vitro and in vivo by inducing apoptosis and profound TS inhibition, and showing a synergistic benefit when combined with nilotinib. These data demonstrate that TS is a valid target in ALL cells. This fact combined with previous studies demonstrating a favorable toxicity profile, make FdUMP[10] a promising candidate for treatment of ALL. Disclosures:Pardee:Salzburg Therapuetics: Membership on an entity's Board of Directors or advisory committees. Gmeiner:Salzburg Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.