Anticancer Agents In Clinical Trials Research Articles

Disproportionality Analysis of Stomatitis Associated with Anticancer Drugs Using the Japanese Adverse Drug Event Report Database

Introduction: Anticancer drug-induced stomatitis can affect a patient’s quality of life and the continuation of drug treatment. Although there have been reports of the occurrence of stomatitis associated with anticancer agents in clinical trials, few Japanese participants have been enrolled in clinical trials and have not been sufficiently investigated. In addition, there has been little attention on research on anticancer drugs associated with stomatitis by patient stratification with different carcinogenic sites. Therefore, the aim of this study was to determine the disproportionality associated with stomatitis for various types of anticancer drugs in different types of cancer patients using the Japanese Adverse Drug Event Report (JADER) database. Methods: The aim of this study was to identify the disproportionality of stomatitis by analyzing the type of anticancer drug and cancer patients using the Japanese Pharmacovigilance Database. Data obtained from spontaneous reports of adverse events with more than 10 stomatitis outbreaks reported in the JADER database between April 2004 and March 2023 were analyzed. The safety signal for an adverse event was defined as the lower limit of the 95% confidence interval of the reported odds ratio of >1. Results: There were 6,178 reports of drugs associated with stomatitis. Among these, 41 drugs were suggested to be associated with stomatitis, and 41 drugs were detected as signals. These drugs were classified based on their efficacy: antipyrimidines (six drugs), folate metabolism antagonists (three drugs), alkylating agents (four drugs), platinum (three drugs), topoisomerase inhibitors (three drugs), microtubule inhibitors (three drugs), mammalian target of rapamycin (mTOR) inhibitors (two drugs), kinase inhibitors (seven drugs), anti-growth factor antibodies (five drugs) immune checkpoint inhibitors (one drug), and others (four drugs). Conclusion: The drugs that may be associated with stomatitis were cell cycle-dependent drugs, epidermal growth factor receptor-tyrosine kinase inhibitors, and mTOR inhibitors. Moreover, this study suggested that anti-growth factor antibodies and immune checkpoint inhibitors may be associated with stomatitis development.

Abstract 3288: A novel and defined TLR3 agonist based anticancer therpay

Abstract Synthetic dsRNA analogs recognized by TLR3 are an attractive adjuvant candidate for fight against intracellular pathogens or tumors, because of their enhanced T cell-mediated and humoral immunities. Although poly(I:C) is a representative dsRNA with potent adjuvanticity, its clinical application has been severely limited due to heterogenicity, inconsistent activity, poor stability, and toxicity. In spite of numerous clinical trials, few products have been approved for human use. To overcome these limitations, we try to develop a novel defined form of TLR3 agonist. A single 275-kDa homogeneous molecule was selected as an alternative of poly IC and its derivatives and named NexaVant (NVT). The analytical analyses including reverse phase-HPLC analysis demonstrated that NVT is homologous without a lot-to-lot variation. NVT appears to be stable since its appearance, concentration, and molecular size were unaffected under 6 months of accelerated storage conditions. Moreover, preclinical evaluation of toxicity under good laboratory practices showed that NVT is a safe substance without signs of serious toxicity. NVT increases the expression of dsRNA sensors such as TLR3, MDA-5, and RIG-I. Together with a potent apoptotic cell death to several cancer cell lines, NVT substantially induced the phenotypic markers of DC maturation and activation including MHC-II, CD40, CD80, and CD86 together with IFN-alpha production. Several poly IC and its derivatives are used as a in situ anticancer agent in clinical trials. NexaVant was tested as an in-situ cancer therapy reagent in several animal models. When NVT is injected into tumors, it induces and recruits diverse immune cells with a potent anti-cancer effect. Combined with anit-PD-1 antibody, it shows the increase number of DC and T-cells, especially CD8 T cells and decrease that of Tregs. Using human PD-1 knock-in mouse model, NVT has shown the synergistic anti-cancer effect with anti-PD-1 antibody. Several animal efficacy data target to head and neck cancer, triple-negative breast cancer, and melanoma would be presented. Citation Format: Dongho Kim, Sungwhan Lee. A novel and defined TLR3 agonist based anticancer therpay [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 3288.

Abstract 4976: Preclinical characterization of BGI-9004, a covalent TEAD inhibitor with exceptional anti-cancer activity and combination potential

Abstract Pharmacological inhibitors of TEAD transcription factors have emerged as a promising novel class of anti-cancer agents. TEAD inhibitors disrupt oncogenic YAP/TAZ signaling, resulting in cell cycle arrest and cell death in susceptible cancers. In preclinical models, cancer cell lines with alterations in the Hippo signaling pathway, such as mutations or loss of NF2 or LATS, are particularly sensitive to inhibition of TEAD signaling. In addition, YAP/TAZ-TEAD signaling is thought to play a role in resistance to several targeted therapies, such as EGFR inhibitors and MEK inhibitors. BGI-9004 is a covalent inhibitor of TEAD1-4 with low nanomolar potency in a TEAD reporter cell line and anti-cancer activity in vitro and in vivo. In the NF2-deficient NCI-H226 and the NF2-wildtype, LATS-mutant MST-O211H mesothelioma xenograft models, BGI-9004 treatment resulted in sustained tumor regressions over a 28d treatment course. Anti-cancer activity was accompanied by significant inhibition of TEAD-mediated transcription in BGI-9004-treated tumors, and no adverse effects on the body weight of treated mice were observed. Moreover, proteome-wide protein binding of BGI-9004 was assessed by Isobaric Mass Tagged Affinity Characterization (IMTACTM), which confirmed its high selectivity for TEAD. In line with this, BGI-9004 had a clean profile in a panel of protein targets that present potential safety liabilities (CEREP safety panel). These findings prompted us to explore the combination potential of BGI-9004 with other targeted therapies, including inhibitors of EGFR, MEK and mutant KRASG12C. Here, we found that BGI-9004 potentiated the effect of other targeted therapies. In particular, we generated dose response matrices for BGI-9004 and inhibitors of KRASG12C and KRASG12D in several KRAS-mutant cell lines, including three lung cancer cell lines, and demonstrated synergy for the combination. These results suggest that inhibition of YAP/TAZ-TEAD signaling may improve the efficacy of KRAS-targeted therapy. Taken together, the covalent TEAD inhibitor BGI-9004 has demonstrated promising activity both as a single agent and in combination with other targeted agents, a favorable pharmacokinetic profile and high target selectivity in preclinical models, supporting its evaluation as a novel anti-cancer agent in clinical trials. Citation Format: Shirley Guo, Shashank Shrishrimal, Jason Cui, Guoqing Wang, Vivian Zhang, Ning Deng, Iris Dong, Anna Chen, Steve Luo, David Sperandio, Ping Cao, Wolf R. Wiedemeyer. Preclinical characterization of BGI-9004, a covalent TEAD inhibitor with exceptional anti-cancer activity and combination potential. [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 4976.

The efficacy of applying some plants and herbs in cancer therapy for humans and animals – A comprehensive review

Abstract Cancer is a challenging ailment and represents the main reason for death worldwide for humans and animals. Although great developments have hindered cancer progression, several adverse effects are associated with modern chemotherapy. Natural remedies, such as the usage of medicinal plant or their products in cancer treatment, may decrease prejudicial side properties. Recently, the modern research scheme and innovative screening practices for herbs or plants have enabled phytochemical discovery for the prevention and treatment of cancer. This criticism highlights herbs such as acacia, basil, black seeds, cedar, castus, ficus, garlic, ginger, indigo, onion, pomegranate, quince, and thyme, promising anticancer effects. The present review also revealed the mode of action of each herb as anticancer effects at level in vitro and in vivo studies. The item also totalizes the vital mechanisms and signaling molecules involved in preventing cancer diseases. This will fill the investigation gap in the exploration of using natural molecules and encourage researchers in clinical trials of anticancer agents from herbs for humans and animals.

Brain-Targeted Codelivery of Bcl-2/Bcl-xl and Mcl-1 Inhibitors by Biomimetic Nanoparticles for Orthotopic Glioblastoma Therapy.

Glioblastoma (GBM) is among the most treatment-resistant solid tumors and often recurrs after resection. One of the mechanisms through which GBM escapes various treatment modalities is the overexpression of anti-apoptotic Bcl-2 family proteins (e.g., Bcl-2, Bcl-xl, and Mcl-1) in tumor cells. Small-molecule inhibitors such as ABT-263 (ABT), which can promote mitochondrial-mediated cell apoptosis by selectively inhibiting the function of Bcl-2 and Bcl-xl, have been proven to be promising anticancer agents in clinical trials. However, the therapeutic prospects of ABT for GBM treatment are hampered by its limited blood-brain barrier (BBB) penetration, dose-dependent thrombocytopenia, and the drug resistance driven by Mcl-1, which is overexpressed in GBM cells and further upregulated upon treatment with ABT. Herein, we reported that the Mcl-1-specific inhibitor A-1210477 (A12) can act synergistically with ABT to induce potent cell apoptosis in U87 MG cells, drug-resistant U251 cells, and patient-derived GBM cancer stem cells. We further designed a biomimetic nanomedicine, based on the apolipoprotein E (ApoE) peptide-decorated red blood cell membrane and pH-sensitive dextran nanoparticles, for the brain-targeted delivery of ABT and A12. The synergistic anti-GBM effect was retained after encapsulation in the nanomedicine. Additionally, the obtained nanomedicine possessed good biocompatibility, exhibited efficient BBB penetration, and could effectively suppress tumor growth and prolong the survival time of mice bearing orthotopic GBM xenografts without inducing detectable adverse effects.

Role of Phytochemicals in Cancer Chemoprevention: Insights

Cancer is a condition where the body cells multiply in an uncontrollable manner. Chemoprevention of cancer is a broad term that describes the involvement of external agents to slow down or suppress cancer growth. Synthetic and natural compounds are found useful in cancer chemoprevention. The occurrence of global cancer type varies, depending on many factors such as environmental, lifestyle, genetic etc. Cancer is often preventable in developed countries with advanced treatment modalities, whereas it is a painful death sentence in developing and low-income countries due to the lack of modern therapies and awareness. One best practice to identify cancer control measures is to study the origin and risk factors associated with common types. Based on these factors and the health status of patients, stage, and severity of cancer, type of treatment is decided. Even though there are well-established therapies, cancer still stands as one of the major causes of death and a public health burden globally. Research shows that most cancers can be prevented, treated, or the incidence can be delayed. Phytochemicals from various medicinal plants were reported to reduce various risk factors associated with different types of cancer through their chemopreventive role. This review highlights the role of bioactive compounds or natural products from plants in the chemoprevention of cancer. There are many plant based dietary factors involved in the chemoprevention process. The review discusses the process of carcinogenesis and chemoprevention using plants and phytocompounds, with special reference to five major chemopreventive phytocompounds. The article also summarizes the important chemopreventive mechanisms and signaling molecules involved in the process. Since the role of antioxidants in chemoprevention is inevitable, an insight into plant-based antioxidant compounds that fight against this dreadful disease at various stages of carcinogenesis and disease progression is discussed. This will fill the research gap in search of chemopreventive natural compounds and encourage scientists in clinical trials of anticancer agents from plants.

Targeted Mass Spectrometry Enables Quantification of Novel Pharmacodynamic Biomarkers of ATM Kinase Inhibition

Simple SummaryFunctionality of the cellular DNA damage response (DDR) network affects risk for developing cancer, and the DDR is also a target of cancer therapies. Thus, it is important that we have reliable laboratory methods for determining the activity of this network. We describe the development and analytical validation of a targeted mass spectrometry-based 51-plex assay (DDR-2) for measuring proteins and post-translational modifications related to the DDR. The findings demonstrate identification of potential novel pharmacodynamic biomarkers.The ATM serine/threonine kinase (HGNC: ATM) is involved in initiation of repair of DNA double-stranded breaks, and ATM inhibitors are currently being tested as anti-cancer agents in clinical trials, where pharmacodynamic (PD) assays are crucial to help guide dose and scheduling and support mechanism of action studies. To identify and quantify PD biomarkers of ATM inhibition, we developed and analytically validated a 51-plex assay (DDR-2) quantifying protein expression and DNA damage-responsive phosphorylation. The median lower limit of quantification was 1.28 fmol, the linear range was over 3 orders of magnitude, the median inter-assay variability was 11% CV, and 86% of peptides were stable for storage prior to analysis. Use of the assay was demonstrated to quantify signaling following ionizing radiation-induced DNA damage in both immortalized lymphoblast cell lines and primary human peripheral blood mononuclear cells, identifying PD biomarkers for ATM inhibition to support preclinical and clinical studies.

Combined treatment of mitoxantrone sensitizes breast cancer cells to rapalogs through blocking eEF-2K-mediated activation of Akt and autophagy

Oncogenic activation of the mTOR signaling pathway occurs frequently in tumor cells and contributes to the devastating features of cancer, including breast cancer. mTOR inhibitors rapalogs are promising anticancer agents in clinical trials; however, rapalogs resistance remains an unresolved clinical challenge. Therefore, understanding the mechanisms by which cells become resistant to rapalogs may guide the development of successful mTOR-targeted cancer therapy. In this study, we found that eEF-2K, which is overexpressed in cancer cells and is required for survival of stressed cells, was involved in the negative-feedback activation of Akt and cytoprotective autophagy induction in breast cancer cells in response to mTOR inhibitors. Therefore, disruption of eEF-2K simultaneously abrogates the two critical resistance signaling pathways, sensitizing breast cancer cells to rapalogs. Importantly, we identified mitoxantrone, an admitted anticancer drug for a wide range of tumors, as a potential inhibitor of eEF-2K via a structure-based virtual screening strategy. We further demonstrated that mitoxantrone binds to eEF-2K and inhibits its activity, and the combination treatment of mitoxantrone and mTOR inhibitor resulted in significant synergistic cytotoxicity in breast cancer. In conclusion, we report that eEF-2K contributes to the activation of resistance signaling pathways of mTOR inhibitor, suggesting a novel strategy to enhance mTOR-targeted cancer therapy through combining mitoxantrone, an eEF-2K inhibitor.

Cannabis use patterns and patient reported outcomes in oncology and hematology patients: An anonymous survey.

e24143 Background: In a contemporary era of rapidly evolving social and regulatory changes, it is important to understand and characterize patient (pt) cannabis usage and response. Methods: In order to avoid responding bias, we performed the first ever anonymous survey in consecutive patients (pts) cared for in a City of Hope practice site in California. We analyzed demographic information, qualifying conditions, symptoms, and the cannabis product used. Pt reported outcomes of response to cannabis were collected. Improvement in control of symptoms was defined as pts choosing “total” or “a lot”. Results were tabulated and analyzed by the Chi-squared and Fisher’s Exact statistics. Results: 154 of 176 consecutive patients agreed to participate (87.5%). 72.7% had a malignancy (CA), 18.1% non-malignant hematologic disease (HEME), and 10.3% had other illnesses (OTHER). Age was < 45 in 10.3%, 45-64 in 37.0%, and > 64 in 52.6%. Older pts more frequently had CA (32.5% < 45, 70.2% 45-64, vs 81.5% > 64p = .0012). 41.8% were male. Cannabis use was reported in 24.7%. Surprisingly, this did not vary significantly by age (37.5% age < 45, 28.0% age 45-64, and 19.8% age > 64 p = .24), by disease (CA 22.9%, HEME 34.6%, OTHER 28.6% p = .41), nor by gender (male 21.9%, female 25.8% p = .57). Pts used cannabis to control their disease in 42.1%, GI symptoms (nausea, vomiting) in 28.9%, weight loss in 10.5%, fatigue in 42.1%, pain in 73.6%, and other symptoms in 36.8%. Cannabis product was marijuana (MJ) in 32%, CBD in 58% and THC in 8% and varied by age (p = .0006) but not by illness or gender. Improvement in disease was reported in 62.5%, GI symptoms in 63.6%, weight loss in 50%, fatigue in 50%, and pain in 60.7%. Symptom improvement trend was numerically higher with MJ or THC (71%) vs CBD (47%, p = .27). 73% of pts reported they would participate in a cannabis clinical trial. Conclusions: There is a high usage of cannabis. While cannabis use does not vary by age, preference for cannabis product however does vary by age. Pts reported high response rates for various symptoms, which can confound the effectiveness of anticancer or supportive medications. Clinical trials of anticancer agents should stratify by use of cannabis products to avoid misattribution of antitumor effects or side effects. Since cannabis access is expanding across the country, it provides an opportunity to perform randomized trials looking into benefits and risks of cannabis use, and dose and administration methods. Clinicians should screen for cannabis use and document it in social histories separate from the category of illegal drug use.

Impact of Hepatitis Virus on the Feasibility and Efficacy of Anticancer Agents in Patients With Hepatocellular Carcinoma in Phase I Clinical Trials.

Chronic viral hepatitis is a risk factor for liver fibrosis and hepatocellular carcinoma (HCC). Patients with advanced HCC have limited effective therapeutic options and are considered potential candidates for early phase clinical trials of anti-cancer agents. The impact of chronic viral hepatitis on the efficacy of anticancer agents for patients with HCC in phase I trials (P-Is) still remains unclear and has not been reported. We retrospectively analyzed the outcomes of consecutive HCC patients in P-Is conducted in a single institute, focusing on chronic viral hepatitis. Of 85 patients enrolled in P-Is, 46 (54%) patients positive and 39 (46%) patients negative for chronic viral hepatitis showed no significant difference in clinical and laboratory variables and on the point of the best response based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria; moreover, the frequency of Grade ≥3 adverse events (AE) was not significantly different. The median time to treatment failure (TTF) and overall survival (OS) from the P-I enrolment were 2.0 and 13.7 months, respectively. No patient experienced reactivation of hepatitis B virus (HBV) or treatment-related death. Chronic viral hepatitis does not independently affect the outcomes of anticancer drugs. Advanced HCC patients with chronic viral hepatitis could be feasible for P-Is.

Oncolytic cancer therapy with a vaccinia virus strain.

Oncolytic vaccinia virus is currently undergoing evaluation as a biological anticancer agent in clinical trials. This treatment exploits the lytic nature of a viral infection to eradicate the tumor mass in a cancer cell‑specific manner. So far, various vaccinia strains have been used as backbones in the design of oncolytic agents. However, the efficacy as oncolytic virotherapy of Chinese vaccinia strain Tian Tan(VTT) has not been reported. Vaccinia strain Guang9(VG9), derived from VTT by consecutive plaque‑cloning selection, was attenuated to a greater extent than its parental strain. In this study, the oncolytic efficacy of VG9 was evaluated. We examined in vitro replication and cytotoxicity, in vivo biodistribution, and antitumor effects in a B16 tumor model. The results revealed that VG9 replicated rapidly, but the cytotoxicity varied in different cell lines. Significant antitumor effects of VG9 were observed in a murine melanoma tumor model, and an antitumor cytotoxic T‑lymphocyte response induced by VG9 was also observed. The results indicated that the Chinese vaccinia strain VG9 holds promise in the construction of a recombinant vaccinia virus vector and as a potential therapeutic strategy in cancer treatment.

A452, an HDAC6-selective inhibitor, synergistically enhances the anticancer activity of chemotherapeutic agents in colorectal cancer cells.

Although histone deacetylase inhibitors (HDACi) alone could be clinically useful, these are most recently used in combination with other anticancer agents in clinical trials for cancer treatment. Recently, we reported the anticancer activity of an HDAC6-selective inhibitor A452 toward various cancer cell types. This study aims to present a potent synergistic antiproliferative effect of A452/anticancer agent treatment in colorectal cancer cells (CRC) cells, independently of the p53 status. A452 in combination with irinotecan, or SAHA is more potent than either drug alone in the apoptotic pathway as evidenced by activated caspase-3 and PARP, increased Bak and pp38, decreased Bcl-xL, pERK, and pAKT, and induced apoptotic cells. Furthermore, A452 enhances DNA damage induced by anticancer agents as indicated by the increased accumulation of γH2AX and the activation of the checkpoint kinase Chk2. The silencing of HDAC6 enhances the cell growth inhibition and cell death caused by anticancer agents. In addition, A452 induces the synergistic suppression of cell migration and invasion. This study suggests a mechanism by which HDAC6-selective inhibition can enhance the efficacy of specific anticancer agents in CRC cells.

Race-, Age-, and Gender-Based Characteristics and Toxicities of Targeted Therapies on Phase I Trials

Background: The impact of age-, gender-, and race-based differences on safety and efficacy in phase I clinical trials has not been well studied. Methods: We analyzed data from phase I clinical trials evaluating targeted biologic agents in patients with advanced solid malignancies. Race and gender distribution of enrolled patients was compared to the referral population demographics at the city, metro, and state levels. The association between age, gender, and race with type, frequency, and severity of treatment-emergent toxicities and clinical benefit was assessed using univariate and multivariable models. Results: Data from 117 eligible patients – Blacks/Caucasians/Others (27/85/5); male/female (66/51) – were obtained. Blacks were younger than Caucasian patients (median age of 56 vs. 62 years, p = 0.004). Nausea/vomiting was more frequent in female patients (43 vs. 24%, p = 0.03), while hematologic toxicity was more likely in Whites. While median time on treatment was comparable (113 vs. 91; p = 0.840), the median overall survival was significantly shorter for Blacks versus Caucasians (7.4 vs. 11.4 months; p = 0.0227). Black race (HR 2.11; 95% CI 1.24–3.60; p = 0.006) and older age (HR 1.03; 95% CI 1.00–1.06; p = 0.029) were associated with an increased risk of death. Conclusions: Age-, gender-, and race-based disparities were observed with specific toxicity and survival outcomes on phase I clinical trials of anticancer agents.

Action of YM155 on clear cell renal cell carcinoma does not depend on survivin expression levels.

The dioxonapthoimidazolium YM155 is a survivin suppressant which has been investigated as an anticancer agent in clinical trials. Here, we investigated its growth inhibitory properties on a panel of immortalized and patient derived renal cell carcinoma (RCC) cell lines which were either deficient in the tumour suppressor von Hippel-Lindau (VHL) protein or possessed a functional copy. Neither the VHL status nor the survivin expression levels of these cell lines influenced their susceptibility to growth inhibition by YM155. Of the various RCC lines, the papillary subtype was more resistant to YM155, suggesting that the therapeutic efficacy of YM155 may be restricted to clear cell subtypes. YM155 was equally potent in cells (RCC786.0) in which survivin expression had been stably silenced or overexpressed, implicating a limited reliance on survivin in the mode of action of YM155. A follow-up in-vitro high throughput RNA microarray identified possible targets of YM155 apart from survivin. Selected genes (ID1, FOXO1, CYLD) that were differentially expressed in YM155-sensitive RCC cells and relevant to RCC pathology were validated with real-time PCR and western immunoblotting analyses. Thus, there is corroboratory evidence that the growth inhibitory activity of YM155 in RCC cell lines is not exclusively mediated by its suppression of survivin. In view of the growing importance of combination therapy in oncology, we showed that a combination of YM155 and sorafenib at ½ x IC50 concentrations was synergistic on RCC786.0 cells. However, when tested intraperitoneally on a murine xenograft model derived from a nephrectomised patient with clear cell RCC, a combination of suboptimal doses of both drugs failed to arrest tumour progression. The absence of synergy in vivo highlighted the need to further optimize the dosing schedules of YM155 and sorafenib, as well as their routes of administration. It also implied that the expression of other oncogenic proteins which YM155 may target is either low or absent in this clear cell RCC.

Early phase clinical trials of anticancer agents in children and adolescents - an ITCC perspective.

In the past decade, the landscape of drug development in oncology has evolved dramatically; however, this paradigm shift remains to be adopted in early phase clinical trial designs for studies of molecularly targeted agents and immunotherapeutic agents in paediatric malignancies. In drug development, prioritization of drugs on the basis of knowledge of tumour biology, molecular 'drivers' of disease and a drug's mechanism of action, and therapeutic unmet needs are key elements; these aspects are relevant to early phase paediatric trials, in which molecular profiling is strongly encouraged. Herein, we describe the strategy of the Innovative Therapies for Children with Cancer (ITCC) Consortium, which advocates for the adoption of trial designs that enable uninterrupted patient recruitment, the extrapolation from studies in adults when possible, and the inclusion of expansion cohorts. If a drug has neither serious dose-related toxicities nor a narrow therapeutic index, then studies should generally be started at the adult recommended phase II dose corrected for body surface area, and act as dose-confirmation studies. The use of adaptive trial designs will enable drugs with promising activity to progress rapidly to randomized studies and, therefore, will substantially accelerate drug development for children and adolescents with cancer.

Artemisinin and its derivatives in cancer therapy: status of progress, mechanism of action, and future perspectives

Since the late 1990s, there has been rapid multiplication of data on the anti-cancer properties of artemisinins. This article reviews the status of progress of artemisinin and its derivatives as anti-cancer agents in clinical trials, case reports, and in vitro/in vivo studies. Particular attention is laid on the combinations of artemisinins and synthetic chemodrugs to enhance the latter's efficacy. An attempt is here made to rationalize the synergistic effects of a few common anti-cancer drugs of the anthracycline, taxane, anti-metabolite, and platinum-based drug families. The various pathways that mediate the action of artemisinins as reported over the past decade are here summarized highlighting also the biomarkers that could be used to better predict the efficacy of the sesquiterpenoids. Their main action seems to be directed toward stalling tumor cell proliferation through cell cycle arrest mediated by reactive oxygen species (ROS). The emergence of artemisinins' nano-based formulations in combination with chemodrugs to enhance drug bioavailability and targeting as well as immunotherapy is also reviewed. The enhanced efficacy of artemisinin dimers compared to the parent molecules and standard chemotherapy is analyzed. While these therapies hold promises, it may be premature to conclude on their efficacy in the absence of clinical studies.

Abstract P5-15-08: A phase 2 study of eribulin as early-line treatment for HER2- MBC: Evaluation of efficacy, toxicity, and patient-reported outcomes

Abstract Background: Patient-reported outcomes (PROs) independently and directly describe patient (pt) treatment experiences, complement clinician reports, and are increasingly included in drug development. Eribulin (E) has activity in metastatic breast cancer (MBC) previously treated with > 2 regimens. Limited data are available on the activity of E in earlier lines. This phase II single arm study evaluated the activity, safety, and PROs of E in an earlier line setting for HER2- MBC. Methods: Eligible pts had HER2- MBC, 0-1 prior lines of chemotherapy, and enrolled into one of two parallel cohorts: HR+, TNBC. E was dosed 1.4 mg/m2 weekly, 2 wk on/1 wk off; 1 cycle = 3 wks. The primary objective was overall response rate (ORR); additional objectives included progression-free survival (PFS) and safety. Correlative PRO endpoints included description and comparison of toxicity evaluation by PROs vs provider-report for degree of concordance or divergence for each class of toxicity, and description of QOL over time. Neuropathy was evaluated by the FACT-Neurotoxicity subscale, as well as exploration of predictive host polymorphisms. PRO instruments (PRO-CTCAE, FACT-B and FACT-NTX) were administered electronically at baseline, cycles 1-3, then every other cycle. Results: 83 pts enrolled: 45 HR+ and 38 TNBC. Median age was 56 (range: 34-87). 55.4% were first line, and 66% had received previous taxane in the adjuvant or metastatic setting. ORR for all pts was 25.3% (90% CI: 18%-34%); 35.6% in HR+ (90% CI: 24%-49%) and 13.2% in TNBC (90% CI: 5%-26%). mPFS estimate was 5.8 months (mo) for all pts, HR+ 6.2 mo (90% CI: 5.9-8.7) and TNBC 4.0 mo (90% CI: 3.5-4.8). Related toxicities occurring in > 20% of pts were: fatigue (61.4% overall, 32.5% G1, 27.7% G2, 1.2% G3), alopecia (51.8% overall, 16.9% G1, 32.5% G2), nausea (39.8% overall; 26.5% G1, 12.0% G2, 1.2% G3), peripheral sensory neuropathy (36.1% overall; 18.1% G1, 13.3% G2, 4.8% G3), decreased neutrophil count (32.5% overall; 3.6% G1; 4.8% G2, 13.3% G3, 10.8% G4), peripheral motor neuropathy (22.9% overall, 13.3% G1, 6.0% G2, 3.6% G3), and mucositis (20.5% overall, 16.9% G1, 2.4% G2, 1.2% G3). FACT-B Breast Cancer Concern (BCC) and Trial Outcome Index (TOI) scores were stable during therapy. The greatest mean improvement in summed BCC (mean change 3.3) and TOI (mean change 7.9) compared to baseline occurred at cycle 9 in pts with stable disease. Changes from baseline in the NTX and TOI of FACT-NTX worsened during the first 7 cycles of therapy (mean changes NTX 5.3, TOI 4.8). Pharmacogenomic analysis exploring host polymorphisms and development of neuropathy is ongoing. Conclusions: PROs are indispensable in the evaluation of anti-cancer agents in clinical trials. In this phase II trial, E demonstrated activity and safety in early lines of therapy for HER2- MBC. Additionally, improved QOL metrics were observed among pts experiencing stable disease. CTCAE rates of severe neuropathy were low, however PRO testing by FACT-NTX highlights progressive worsening of neurotoxicity. In contrast to classic CTCAE criteria producing aggregate estimates of toxicity, this phase II trial shows longitudinal collection of PROs provides meaningful, complementary, and dynamic clinical information. Citation Format: Metzger O, Lin NU, Schneider B, Faggen M, Come S, Openshaw T, Constantine M, Walsh J, Giobbie-Hurder A, Burstein HJ, Mayer EL. A phase 2 study of eribulin as early-line treatment for HER2- MBC: Evaluation of efficacy, toxicity, and patient-reported outcomes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-15-08.

Doxycycline directly targets PAR1 to suppress tumor progression.

Doxycycline have been reported to exert anti-cancer activity and have been assessed as anti-cancer agents in clinical trials. However, the direct targets of doxycycline in cancer cells remain unclear. In this study, we used a chemical proteomics approach to identify the Protease-activated receptor 1 (PAR1) as a specific target of inhibition of doxycycline. Binding assays and single-molecule imaging assays were performed to confirm the inhibition of doxycycline to PAR1. The effect of doxycycline on multi-omics and cell functions were assessed based on a PAR1/thrombin model. Molecular docking and molecular dynamic simulations revealed that doxycycline interacts with key amino acids in PAR1. Mutation of PAR1 further confirmed the computation-based results. Moreover, doxycycline provides highly selective inhibition of PAR1 signaling in tumors in vitro and in vivo. Using pathological clinical samples co-stained for doxycycline and PAR1, it was found that doxycycline fluorescence intensity and PAR1 expression shown a clear positive correlation. Thus, doxycycline may be a useful targeted anti-cancer drug that should be further investigated in clinical trials.

Preparation, geometric structure, molecular docking thermal and spectroscopic characterization of novel Schiff base ligand and its metal chelates

The condensation of o-benzoyl benzoic acid and 4-aminoantipyrine resulted in the formation of novel Schiff base ligand (HL) with the IUPAC name 2-(((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)imino)(phenyl)methyl)benzoic acid. The synthesized Schiff base ligand and its complexes with M(II)/(III) transition elements (Cr(III), Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II)) were characterized by elemental, magnetic susceptibility, molar conductivity, spectroscopic (1H NMR, mass, UV–visible, FTIR, ESR), thermal and X-ray powder diffraction. The data showed that the complexes had composition of the MHL type. The diffused reflectance spectra, magnetic susceptibility and ESR spectral data of the complexes confirm an octahedral geometry around metal ions. The thermal analysis data revealed the decomposition of the complexes in three to five successive decomposition steps within the temperature range of 30–1000°C, and the activation thermodynamic parameters were reported. The molecular structures of the Schiff base ligand and its Mn(II) and Zn(II) metal complexes are optimized theoretically, and the quantum chemical parameters are calculated. In order to predict the binding between o-benzoyl benzoic acid, 4-aminoantipyrine and HL ligand with the Escherichia coli bacterial RNA (4p20) receptor, molecular docking was carried out. The in vitro antimicrobial screening of the newly synthesized compounds was tested against different bacterial and fungal organisms. The results showed that the metal complexes have biologically activity more than the new Schiff base ligand against the tested organisms. The Schiff base ligand and its complexes were also screened for their anticancer activity against breast cancer cell line (MCF7). The Mn(II), Cr(III) and Cd(II) complexes were found to have low IC50 values which support the possibility of using them as cytotoxic agents and hence might become good anticancer agent in clinical trials.

Investigation of the Structure-Activity Relationships of Aza-A-Ring Indenoisoquinoline Topoisomerase I Poisons.

Several indenoisoquinolines have shown promise as anticancer agents in clinical trials. Incorporation of a nitrogen atom into the indenoisoquinoline scaffold offers the possibility of favorably modulating ligand-binding site interactions, physicochemical properties, and biological activities. Four series of aza-A-ring indenoisoquinolines were synthesized in which the nitrogen atom was systematically rotated through positions 1, 2, 3, and 4. The resulting compounds were tested to establish the optimal nitrogen position for topoisomerase IB (Top1) enzyme poisoning activity and cytotoxicity to human cancer cells. The 4-aza compounds were the most likely to yield derivatives with high Top1 inhibitory activity. However, the relationship between structure and cytotoxicity was more complicated since the potency was influenced strongly by the side chains on the lactam nitrogen. The most cytotoxic azaindenoisoquinolines 45 and 46 had nitrogen in the 2- or 3-positions and a 3'-dimethylaminopropyl side chain, and they had MGM GI50 values that were slightly better than the corresponding indenoisoquinoline 64.