Cancer Clinical Studies Research Articles

Trilaciclib: First Approval.

Trilaciclib (Cosela™) is a small-molecule, short-acting, inhibitor of cyclin-dependent kinases (CDK) 4 and 6 developed by G1 Therapeutics for its myeloprotection and potential antitumor efficacy and safety benefits in combination with cancer chemotherapy. CDKs govern cell cycle progression, and trilaciclib induces a transient, reversible G1 cell cycle arrest of proliferating haematopoietic stem and progenitor cells in bone marrow, thus protecting them from damage during chemotherapy. In February 2021, trilaciclib received its first approval in the USA to decrease the incidence of chemotherapy-induced myelosuppression in adult patients when administered prior to a platinum/etoposide-containing regimen or topotecan-containing regimen for extensive-stage small cell lung cancer (ES-SCLC). Clinical studies in breast cancer, colorectal cancer and small cell lung cancer are underway in several countries. This article summarizes the milestones in the development of trilaciclib leading to this first approval.

An overview on breast cancer genetics and recent innovations: Literature survey.

Breast cancer is one of the leading cancers nowadays. The genetical mechanism behind breast cancer development is an intricate one. In this review, the genetical background of breast cancer, particularly BRCA 1 and BRCA 2 had been included. Moreover, to summarize the genetics of breast cancer, the recent and ongoing preclinical and clinical studies on the treatment of BRCA-associated breast cancer had also been included. A prime knowledge is that the BRCA gene is the basis of breast cancer risk. How it mediates cell proliferation and associated mechanisms are reviewed here. BRCA 1 gene can influence all phases of the cell cycle and regulate cell cycle progression. BRCA 1 gene can also respond to DNA damages and induce responsive mechanisms. The action of the BRCA gene on associated protein has a wide consideration in breast cancer development. Heterogeneity in breast cancer makes them a fascinating and challenging stream to diagnose and treat. Several clinical therapies are available for breast cancer treatments. Chemotherapy, endocrine therapy, radiation therapy and immunotherapy are the milestones in the cancer treatments. Ral binding protein 1 is a promising target for breast cancer treatment and the platinum-based chemotherapies are the other remarkable fields. In immunotherapy, the usage of anti-programmed death (PD)-1 antibody is a new class of cancer immunotherapy that hinders immune effecter inhibition and potentially expanding preexisting anticancer immune responses. Breast cancer genetics and treatment strategies are crucial in escalating survival rates.

The Intricate Relationship between Melatonin and Breast Cancer: A Short Review.

Melatonin is a relatively recently isolated hormone, produced by the pineal gland. Its implication in several cell functions has augmented interest from scientists worldwide. There is ongoing research investigating the deterrent relationship between melatonin and malignancies and in particular breast cancer. The aim of this article is to review some of the most important findings concerning the effect of melatonin on cancer biology, from both preclinical and clinical studies providing an insight to the complex biological actions of this molecule, as well as their potential significance. The last part concentrates on the oncostatic activities of melatonin on breast cancer and special attention is given on the interplay between melatonin and estrogen. Epidemiological, experimental and clinical evidence indicates that this area is worth further investigation.

Prediction Model for Disease Progression and Relevant Prognostic Factors in Hodgkin Patients: An Application of Frailty Multistate Model

Background: In clinical cancer studies, there has been a high tendency of searching for more specific and new prognostic factors in cancers in the last few years. This multistate study aimed to model the progression of Hodgkin's disease by accounting for individual effect (heterogeneity) using the joint and independent frailty models. Method: After the utilization of the illness-death model, joint-modeling accounted for the dependency between relapse and death by considering the individual characteristics as a frailty term. Therefore, the effect of influential prognostic factors was evaluated on disease progression by frailty and joint-frailty multistate models. Results: The individual predictions were determined using the frameworks of the both models. The model was applied to 389 Hodgkin lymphoma patients. Gender (male), age (over 55 years), and low level of hemoglobin (less than 10.5) were associated with an increased risk of death and relapse in patients. The likelihood cross-validation criterion was proposed to choose the joint frailty model as a better fitting model. Conclusion: Multistate models were appropriate tools to study the whole event history of the subjects, which provided a deep insight into the dynamics of the disease. The problem of events-subjects dependency in the survival data was clarified using the multistate model. Therefore, the heterogeneity and dependency between the states led to more accurate estimations of the effects of the prognostic factors, thereby improving the predictions.

Abstract PS7-34: The association of race and socioeconomic status with overall survival in women with breast cancer in the southern community cohort study

Abstract Background:Breast cancer outcomes in minority and low socioeconomic status populations are not clearly defined due to underrepresentation of these underserved populations in breast cancer clinical trials and population-based studies. The Southern Community Cohort Study (SCCS), a prospective cohort of underserved, predominantly Black participants, provides a unique opportunity to evaluate disparities in breast cancer outcomes. We sought to examine the association between race and socioeconomic status (SES) and overall survival (OS) in women with localized breast cancer in the SCCS. Methods:The SCCS enrolled approximately 86,000 participants aged 40-79 from 12 Southeastern states between 2002-2009, 86% of whom were enrolled at Community Health Centers. This analysis includes women diagnosed with incident localized breast cancer (stage I-III) identified through annual cohort linkage with 12 state cancer registries through December 20, 2017. Demographic data including participant age, self-reported history of diagnosed diabetes, body mass index (BMI), race, annual household income, and insurance coverage were obtained from baseline surveys. Tumor grade and stage were obtained from state cancer registries, and survival data were obtained from death registry records. Immunohistochemical (IHC) subtype was determined from tumor estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status obtained from cancer registry records and pathology reports. Survival time was defined as the number of months between initial breast cancer diagnosis and death from any cause. Descriptive analyses including mean (standard deviation) and number (%) were used to summarize clinical and sociodemographic characteristics by race. Multivariable Cox survival analysis was used to evaluate OS by race and annual household income, adjusting for age, insurance, stage, IHC subtype, diabetes, and BMI. Results:Of the 1347 women diagnosed with incident breast cancer, 1016 had localized disease (stage I-III) and comprised our analytic sample. Compared to White women, Black women were more likely to have lower income, higher prevalence of triple negative breast cancer (TNBC), grade III tumors and stage III breast cancer (Table 1). After adjusting for clinical and sociodemographic factors, Black women had similar OS compared to White women (HR 0.67; 95% CI 0.42-1.07). However, after adjusting for race, women with a household income ≥ $25,000 had an improved OS compared to those with annual household income < $25,000 (HR 0.53; 95% CI 0.30-0.93). Conclusion: In a low-income, medically underserved population, Black women with localized breast cancer had similar OS compared to White women. However, socioeconomic disparities were observed, with worse OS for women with low annual household income. Future studies focused on minority, underserved groups are imperative to better understand the non-biological and biological factors contributing to disparities in survival among women with breast cancer. Table 1. Patient characteristics overall and by racePatient CharacteristicsTotal(N=1016)Black(N=667)White(N=349)P-value*Age at diagnosis, years (Mean, SD)61 (9)60 (9)63 (9)Income, annual household (N, %) < $25,000 ≥ $25,000719 (71)297 (29)503 (75)164 (25)216(62)133 (38)<0.001Insurance (N, %) Private insurance Medicare Medicaid Uninsured220 (29)331 (43)178 (23)34 (5)152 (29)209 (40)139 (26)26 (5)68 (29)122 (51)39 (16)8 (3)0.005Diabetes (N, %) No history of diabetes History of diabetes736 (74)258 (26)469 (72)183 (28)267 (78)75 (22)0.04BMI, kg/m2 (N, %) 18.5-30.0 kg/m2 30.0+ kg/\\411 (40)605 (60)239 (36)428 (64)172 (49)177 (51)<0.001IHC subtype (N, %) HR+,HER2- HR+,HER2+ HR-,HER2- TNBC392 (69)55 (10)34 (6)86 (15)255 (65)38 (10)26 (7)75 (19)137 (79)17 (10)8 (5)11 (6)0.001Grade (N, %) I II III188 (20)383 (41)372 (39)111 (18)239 (38)277 (44)77 (24)144 (46)95 (30)<0.001Stage (N, %) I II III460 (45)383 (38)173 (17)278 (42)261 (39)128 (19)182 (52)122 (35)45 (13)0.003HR = Estrogen receptor (ER) and/or progesterone receptor (PR)* denotes p-value for White compared Black women Citation Format: Sonya Reid, Lucy B Spalluto, Diane Haddad, Tuya Pal, Ingrid Mayer, Xiao-ou Shu, Wei Zheng, Maureen Sanderson, William Blot, Loren Lipworth. The association of race and socioeconomic status with overall survival in women with breast cancer in the southern community cohort study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-34.

The Intricate Relationship between Melatonin and Breast Cancer: A Short Review.

Melatonin is a relatively recently isolated hormone, produced by the pineal gland. Its implication in several cell functions has augmented interest from scientists worldwide. There is ongoing research investigating the deterrent relationship between melatonin and malignancies and in particular breast cancer. The aim of this article is to review some of the most important findings concerning the effect of melatonin on cancer biology, from both preclinical and clinical studies providing an insight to the complex biological actions of this molecule, as well as their potential significance. The last part concentrates on the oncostatic activities of melatonin on breast cancer and special attention is given on the interplay between melatonin and estrogen. Epidemiological, experimental and clinical evidence indicates that this area is worth further investigation.

Detecting the Dark Matter of Unpublished Clinical Cancer Studies: An Analysis of Phase 3 Randomized Controlled Trials

Unpublished randomized controlled trial (RCT) frequency, correlates, and financial impact are not well understood. We sought to characterize the nonpublication of peer-reviewed manuscripts among interventional, therapeutic, multi-arm, phase 3 oncology RCTs. Trials were identified by searching ClinicalTrials.gov, while publications and abstracts were identified through PubMed and Google Scholar. Trial data were extracted from ClinicalTrials.gov and individual publications. Publication was defined as a peer-reviewed manuscript addressing the primary endpoint. Patient accrual cost was extrapolated from experimental data; investigators/sponsors were contacted to determine nonpublication reasons. Six hundred eighty-four completed RCTs met inclusion criteria, which accrued 434,610 patients from 1994 to 2015; 638 were published (93.3%) and 46 were unpublished (6.7%). Among the unpublished trials, the time difference from primary endpoint maturity to data abstraction was a median of 6 years (interquartile range, 4 to 8 years). On multiple binary logistic regression analysis, factors associated with unpublished trials included lack of cooperative group sponsorship (odds ratio, 5.91, 95% CI, 1.35 to 25.97; P=.019) and supportive care investigation (odds ratio, 2.90; 95% CI, 1.13 to 7.41; P=.027). The estimated inflation-adjusted average cost of patient accrual for all unpublished trials was $113,937,849 (range, $41,136,883 to $320,201,063). Direct contact with sponsors/investigators led to a 50.0% response rate (n=23 of 46); manuscript in preparation and/or in submission (n=10 of 23) was the most commonly cited reason for nonpublication. In conclusion, approximately 1 in 15 clinical oncology RCTs are unpublished and this has a profound impact on the research enterprise. The cooperative group infrastructure may serve as a blueprint to reduce nonpublication.

Endoplasmic reticulum stress and organoids

Organoids represent an advanced tool in cell biology and have redefined biomedical research. Organoids are ideal for studies of biological processes, pharmacological studies, and therapeutic research to imitate pathological processes and preserve genetic integrity. The endoplasmic reticulum (ER) is the central organelle responsible for protein folding, post-translational adaptations, and membrane and luminal protein transportation. ER stress is a disorder influenced by a range of physiological and pathological causes, such as nutrient deficiency, impaired glycosylation, calcium depletion, oxidative stress, DNA damage, and energy disruption. Disturbance of the ER environment triggers aggregation of unfolded/misfolded proteins, accelerating ER stress. The unfolded protein response (UPR) is a transduction mechanism that activates cells in response to ER stress to restore ER homeostasis, altering cancer development and progression. However, the mechanisms through which sustained and unresolved UPR signaling triggers a switch from pro-survival to pro-death pathways remain unclear. Immutable and environmental stimuli that modify protein homeostasis are often incorporated into tumor cells, thereby generating ER stress. Herein, we discuss challenges and advances in fundamental and clinical cancer studies on ER stress. Additionally, current trends in organoid technology are summarized to fill the gap in our knowledge of the relationship between cancer and ER stress, with the UPR representing a future tool for investigating drug response screening and potentially revolutionizing the workflow of new cancer drug development.

Encoding DNA Frameworks for Amplified Multiplexed Imaging of Intracellular microRNAs.

Real-time imaging of multiple low-abundance microRNAs (miRNAs) simultaneously in living cells with high sensitivity is of vital importance for accurate cancer clinical diagnosis and prognosis studies. Maintaining stability of nanoprobes resistant to enzyme degradation and enabling effective signal amplification is highly needed for in vivo imaging studies. Herein, a rationally designed one-pot assembled multicolor tetrahedral DNA frameworks (TDFs) by encoding multicomponent nucleic acid enzymes (MNAzymes) was developed for signal-amplified multiple miRNAs imaging in living cells with high sensitivity and selectivity. TDFs could enter cells via self-delivery with good biocompatibility and stability. Two kinds of MNAzymes specific for miRNA-21 and miRNA-155 with fluorescein labeling were encoded in the structure of TDFs respectively through one-step thermal annealing. In the intracellular environment, the TDFs could be specifically bound with its specific miRNA target and form an active DNAzyme structure. The cleavage of the active site would trigger the release of target miRNA and circular fluorescence signal amplification, which enabled accurate diagnosis on miRNA identifications of different cell lines with high sensitivity. Meanwhile, with the specific AS1411 aptamer targeting for nucleolin overexpressed on the surface of the carcinoma cells, this well-designed TDFs nanoprobe exhibited good discrimination between cancer cells and normal cells. The strategy provides an efficient tool for understanding the biological function of miRNAs in cancer pathogenesis and therapeutic applications.

An overview on diagnosis and surgical management of gallbladder cancer

Gallbladder cancer is among the most deadly cancers, and it continues to present surgeons with numerous challenges. Cholelithiasis, an abnormal pancreaticobiliary junction, and focal mucosal microcalcifications are all known risk factors for gallbladder carcinoma. The most common histologic type in most patients is adenocarcinoma, which is frequently associated with Kras and p53 mutations. Endoscopic ultrasonography, magnetic resonance cholangiopancreatography, as well as helical computed tomography, as well as radiologic or endoscopic improvements in endoscopic ultrasonography as well as magnetic resonance cholangialpancratia, have improved preoperative staging. Cholecystectomy (subsegmental surgical excision of segments IVB but instead V plus a hepatoduodenal ligament lymphadenectomy) for advanced disease without indications of distant metastasis (T2–4/N0-N2) or a radical cholecystectomy (subsegmental resection of segments IVB as well as V plus a hepatoduodenal musculotendinous lymphadenectomy) for severe stages without indications of distant metastasis More extensive hepatic resection, such as extended right hepatectomy or central segmentectomy with caudate lobectomy, has been recommended by certain surgeons. Patients who underwent a pancreaticoduodenectomy to enhance distal ductal margins as well as lymphadenectomy for T3 or T4 malignancies were studied by Japanese surgeons. These patients had a reduced incidence of tumor recurrence but no benefit in terms of survival. Adjuvant treatment options are still restricted. The most frequent postoperative treatment is radiation therapy with fluorouracil radio sensitization. Capecitabine, oxaliplatin, & bevacizumab are now being studied in the treatment of gallbladder cancer in clinical studies.

Epigenetic Regulation in Breast Cancer.

Aberrant epigenetic alteration has been associated with development of various cancers, including breast cancer. Since epigenetic modifications such as DNA methylation and histone modification are reversible, epigenetic enzymes, including histone modifying enzymes and DNA methyltransferases, emerge as attractive targets for cancer therapy. Although epi-drugs targeting histone deacetylation or DNA methylation have received FDA approval for cancer therapy, a very modest anti-tumor activity has been observed with monotherapy in clinical studies of breast cancer. To improve efficacy of epi-drugs in breast cancer, combination of epi-drugs with other therapies currently has been investigated. Additionally, basic researches to elucidate molecular causes of cancer should be extensively and intensively conducted in order to find novel epigenetic druggable targets. In this chapter, we summarize how epigenetic regulation affects the development of breast cancer and how to control cancer phenotype by modulating abnormal epigenetic modifications, and then suggest future research directions in epigenetics for breast cancer treatment.

Microbiota and cancer: In vitro and in vivo models to evaluate nanomedicines.

Nanomedicine implication in cancer treatment and diagnosis studies witness huge attention, especially with the promising results obtained in preclinical studies. Despite this, only few nanomedicines succeeded to pass clinical phase. The human microbiota plays obvious roles in cancer development. Nanoparticles have been successfully used to modulate human microbiota and notably tumor associated microbiota. Taking the microbiota involvement under consideration when testing nanomedicines for cancer treatment might be a way to improve the poor translation from preclinical to clinical trials. Co-culture models of bacteria and cancer cells, as well as animal cancer-microbiota models offer a better representation for the tumor microenvironment and so potentially better platforms to test nanomedicine efficacy in cancer treatment. These models would allow closer representation of human cancer and might smoothen the passage from preclinical to clinical cancer studies for nanomedicine efficacy.

Enhanced Detection of Treatment Effects on Metastatic Colorectal Cancer with Volumetric CT Measurements for Tumor Burden Growth Rate Evaluation.

Mathematical models combined with new imaging technologies could improve clinical oncology studies. To improve detection of therapeutic effect in patients with cancer, we assessed volumetric measurement of target lesions to estimate the rates of exponential tumor growth and regression as treatment is administered. Two completed phase III trials were studied (988 patients) of aflibercept or panitumumab added to standard chemotherapy for advanced colorectal cancer. Retrospectively, radiologists performed semiautomated measurements of all metastatic lesions on CT images. Using exponential growth modeling, tumor regression (d) and growth (g) rates were estimated for each patient's unidimensional and volumetric measurements. Exponential growth modeling of volumetric measurements detected different empiric mechanisms of effect for each drug: panitumumab marginally augmented the decay rate [tumor half-life; d [IQR]: 36.5 days (56.3, 29.0)] of chemotherapy [d: 44.5 days (67.2, 32.1), two-sided Wilcoxon P = 0.016], whereas aflibercept more significantly slowed the growth rate [doubling time; g = 300.8 days (154.0, 572.3)] compared with chemotherapy alone [g = 155.9 days (82.2, 347.0), P ≤ 0.0001]. An association of g with overall survival (OS) was observed. Simulating clinical trials using volumetric or unidimensional tumor measurements, fewer patients were required to detect a treatment effect using a volumetric measurement-based strategy (32-60 patients) than for unidimensional measurement-based strategies (124-184 patients). Combined tumor volume measurement and estimation of tumor regression and growth rate has potential to enhance assessment of treatment effects in clinical studies of colorectal cancer that would not be achieved with conventional, RECIST-based unidimensional measurements.

SVM &Ga-clustering Based Feature Selection Approach for Breast Cancer Detection

Mortality leading among women in developed countries is breast cancer. Breast cancer is women's second most prominent cause of cancer mortality worldwide. In recent decades, women's high prevalence of breast cancer has risen dramatically. This paper discussed several data analysis methods used to detect breast cancer early. Breast cancer diagnosis distinguishes benign and malignant breast lumps. Using data processing tools, we tackled this disease analysis. Data mining is an important step of library discovery where intelligent methods are used to detect patterns. Several clinical breast cancer studies were conducted using soft computing and machine learning techniques. Sometimes their algorithms are easier, easier, or more comprehensive than others. This research is focused on genetic programming and machine learning algorithms to reliably identify benign and malignant breast cancer. This study aimed to optimise the testing algorithm. We used genetic programming methods to choose classification machines' best features and parameter values. Data mining is an important step of library discovery where intelligent methods are used to detect patterns. We are analysing data accessible from the U.C.I. deep-learning data set in Wisconsin. In this experiment, we equate four Weka clustering strategies with genetic clustering. A comparison of results reveals that sequential minimal optimization (S.M.O.) is better than I.B.K. and B.F. Tree processes, i.e. 97.71%.

Promising Therapy in Lung Cancer: Spotlight on Aurora Kinases

Simple SummaryLung cancer has remained one of the major causes of death worldwide. Thus, a more effective treatment approach is essential, such as the inhibition of specific cancer-promoting molecules. Aurora kinases regulate the process of mitosis—a process of cell division that is necessary for normal cell proliferation. Dysfunction of these kinases can contribute to cancer formation. In this review, we present studies indicating the implication of Aurora kinases in tumor formation, drug resistance, and disease prognosis. The effectivity of using Aurora kinase inhibitors in the pre-clinical and clinical investigations has proven their therapeutic potential in the setting of lung cancer. This work may provide further information to broaden the development of anticancer drugs and, thus, improve the conventional lung cancer management.Despite tremendous efforts to improve the treatment of lung cancer, prognosis still remains poor; hence, the search for efficacious therapeutic option remains a prime concern in lung cancer research. Cell cycle regulation including mitosis has emerged as an important target for cancer management. Novel pharmacological agents blocking the activities of regulatory molecules that control the functional aspects of mitosis such as Aurora kinases are now being investigated. The Aurora kinases, Aurora-A (AURKA), and Aurora B (AURKB) are overexpressed in many tumor entities such as lung cancer that correlate with poor survival, whereby their inhibition, in most cases, enhances the efficacy of chemo-and radiotherapies, indicating their implication in cancer therapy. The current knowledge on Aurora kinase inhibitors has increasingly shown high potential in ensuing targeted therapies in lung malignancies. In this review, we will briefly describe the biology of Aurora kinases, highlight their oncogenic roles in the pre-clinical and clinical studies in lung cancer and, finally, address the challenges and potentials of Aurora kinases to improve the therapy of this malignancy.

From clinical trials to clinical use of checkpoint inhibitors for patients with metastatic urothelial cancer.

Monoclonal antibodies targeting the checkpoint inhibitors (CPIs), programmed cell death protein-1 or programmed cell death ligand-1, are changing the landscape of urothelial carcinoma therapeutics. Overall, clinical studies in metastatic or advanced urothelial cancer showed that CPIs provided a slight improvement in survival and a relevant advantage in safety, compared with chemotherapy. After reviewing published and ongoing trials, the authors discuss expected answers to unmet needs, with a special attention to the research of biological markers for patients with urothelial cancer eligible for treatment with CPIs in this article.

The Role of PPARγ Ligands in Breast Cancer: From Basic Research to Clinical Studies.

Simple SummaryBreast cancer represents the most frequently diagnosed carcinoma and the leading cause of cancer death in women. Despite advances achieved in systemic therapy, about one-third of all patients relapse and develop a metastatic disease, which ultimately leads to breast cancer deaths. In this scenario, the identification of new prognostic factors and pharmacological tools is needed to improve breast cancer management. Peroxisome proliferator-activated receptor gamma (PPARγ), belonging to the nuclear receptor superfamily, is a ligand-dependent transcription factor expressed in many tumors including breast cancer, and its function upon binding of ligands has been linked to the tumor development, progression and metastasis. Over the last decade, much research has focused on the implication of natural and synthetic PPARγ agonists in the negative regulation of breast cancer growth and progression. The aim of the present review is to summarize the role of PPARγ activation in breast cancer from the basic research to clinical studies. The therapeutic effects of natural and synthetic PPARγ ligands, as antineoplastic agents, represent a fascinating and clinically a potential translatable area of research with regards to the battle against cancer.Peroxisome proliferator-activated receptor gamma (PPARγ), belonging to the nuclear receptor superfamily, is a ligand-dependent transcription factor involved in a variety of pathophysiological conditions such as inflammation, metabolic disorders, cardiovascular disease, and cancers. In this latter context, PPARγ is expressed in many tumors including breast cancer, and its function upon binding of ligands has been linked to the tumor development, progression, and metastasis. Over the last decade, much research has focused on the potential of natural agonists for PPARγ including fatty acids and prostanoids that act as weak ligands compared to the strong and synthetic PPARγ agonists such as thiazolidinedione drugs. Both natural and synthetic compounds have been implicated in the negative regulation of breast cancer growth and progression. The aim of the present review is to summarize the role of PPARγ activation in breast cancer focusing on the underlying cellular and molecular mechanisms involved in the regulation of cell proliferation, cell cycle, and cell death, in the modulation of motility and invasion as well as in the cross-talk with other different signaling pathways. Besides, we also provide an overview of the in vivo breast cancer models and clinical studies. The therapeutic effects of natural and synthetic PPARγ ligands, as antineoplastic agents, represent a fascinating and clinically a potential translatable area of research with regards to the battle against cancer.

A batch-effect adjusted Simon's two-stage design for cancer vaccine clinical studies.

In the development of cancer treatment vaccines, phase II clinical studies are conducted to examine the efficacy of a vaccine in order to screen out vaccines with minimal activity. Immune responses are commonly used as the primary endpoint for assessing vaccine efficacy. With respect to study design, Simon's two-stage design is a popular format for phase II cancer clinical studies because of its simplicity and ethical considerations. Nonetheless, it is not straightforward to apply Simon's two-stage design to cancer vaccine studies when performing immune assays in batches, as outcomes from multiple patients may be correlated with each other in the presence of batch effects. This violates the independence assumption of Simon's two-stage design. In this paper, we numerically explore the impact of batch effects on Simon's two-stage design, propose a batch-effect adjusted Simon's two-stage design, demonstrate the proposed design by both a simulation study and a therapeutic human papillomavirus vaccine trial, and briefly introduce a software that implements the proposeddesign.

Cell proliferation inhibitors and apoptosis promoters

Cancer is characterised by uncontrolled proliferation and prolonged cell survival. In some cases, tumour formation is the result from aberrant activity of various cell-cycle regulators leading to chromosome instability or from alteration of the apoptosis pathway. Ovarian cancer is an entity in which cell-cycle alterations are common. P53, a key regulator of checkpoint G1, is frequently altered in high-grade serous ovarian cancer. Targeting cell-cycle regulators will lead to mitotic catastrophe and cell death in these tumours. Promoting apoptosis is another target that is gaining interest in ovarian cancer.In this review, the most relevant evidence of clinical studies in ovarian cancer with compounds targeting cell cycle or promoting apoptosis is summarised.

EZH2 inhibition: apromisingstrategy to prevent cancer immune editing.

Immunotherapies are revolutionizing the clinical management of a wide range of cancers. However, intrinsic or acquired unresponsiveness to immunotherapies does occur due to the dynamic cancer immunoediting which ultimately leads to immune escape. The evolutionarily conserved histone modifier enhancer of zeste 2 (EZH2) is aberrantly overexpressed in a number of human cancers. Accumulating studies indicate that EZH2 is a main driver of cancer cells' immunoediting and mediate immune escape through downregulating immune recognition and activation, upregulating immune checkpoints and creating an immunosuppressive tumor microenvironment. In this review, we overviewed the roles of EZH2 in cancer immunoediting, the preclinical and clinical studies of current pharmacologic EZH2 inhibitors and the prospects for EZH2 inhibitor and immunotherapy combination for cancer treatment.