Genomic landscape of patients in a phase II study of zanubrutinib in ibrutinib- and/or acalabrutinib-intolerant patients with B-cell malignancies.

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Zanubrutinib in patients with previously treated B-cell malignancies intolerant of previous Bruton tyrosine kinase inhibitors in the USA: a phase 2, open-label, single-arm study.

BACKGROUND: We hypothesised that zanubrutinib, a highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor, would be a safe and active treatment for patients intolerant of ibrutinib, acalabrutinib, or both. We aimed to assess whether zanubrutinib would prolong treatment duration by minimising treatment-related toxicities and discontinuations in patients with previously treated B-cell malignancies. METHODS: This ongoing, phase 2, multicentre, open-label, single-arm study was done in 20 centres in the USA. Patients aged 18 or older with previously treated B-cell malignancies (chronic lymphocytic leukaemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinaemia, or marginal zone lymphoma) who became intolerant of ibrutinib, acalabrutinib, or both, were orally administered zanubrutinib 160 mg twice daily or 320 mg once daily per investigator. The primary endpoint was recurrence and change in severity of ibrutinib or acalabrutinib intolerance events based on investigator-assessed adverse events. Secondary endpoints were investigator-assessed overall response rate; duration of response; disease control rate; and progression-free survival. Analyses included all patients who received any dose of the study drug. This study is registered with ClinicalTrials.gov, NCT04116437. FINDINGS: Between Oct 14, 2019, and Sept 8, 2021, 67 patients (36 [54%] men and 31 [46%] women) who were intolerant of ibrutinib (n=57; cohort 1) or of acalabrutinib or acalabrutinib and ibrutinib (n=10; cohort 2) were enrolled. 63 (94%) patients were White, one (2%) had multiple ethnicities, and three (5%) had unreported or unknown ethnicity. Most intolerance events (81 [70%] of 115 for ibrutinib; 15 [83%] of 18 for acalabrutinib) did not recur with zanubrutinib. Of the recurring events, seven (21%) of 34 ibrutinib intolerance events and two (67%) of three acalabrutinib intolerance events recurred at the same severity with zanubrutinib; 27 (79%) ibrutinib intolerance events and one (33%) acalabrutinib intolerance event recurred at a lower severity with zanubrutinib. No events recurred at higher severity. No grade 4 intolerance events recurred. 64 (96%) of 67 patients had one or more adverse events with zanubrutinib; the most common adverse events were contusion (in 15 [22%] of 67 patients), fatigue (14 [21%]), myalgia (ten [15%]), arthralgia (nine [13%]), and diarrhoea (nine [13%]). Atrial fibrillation occurred in three (4%) patients (all grade 2). Eight (12%) of 67 patients had serious adverse events (anaemia, atrial fibrillation, bronchitis, COVID-19, COVID-19 pneumonia, febrile neutropenia, salmonella gastroenteritis, transfusion reaction, trigeminal nerve disorder, and urinary tract infection). No treatment-related deaths occurred. The median follow-up time was 12·0 months (IQR 8·2-15·6). Among the 64 efficacy-evaluable patients, disease control rate was 93·8% (60; 95% CI 84·8-98·3) and overall response rate was 64·1% (41; 95% CI 51·1-75·7). The median duration of response was not reached; the 12-month event-free duration of response rate was 95·0% (95% CI 69·5-99·3). Similarly, median progression-free survival was not reached; 18-month progression-free survival was 83·8% (95% CI 62·6-93·6). INTERPRETATION: Patients intolerant of previous BTK inhibitors have limited treatment options. These results suggest that zanubrutinib, a safe and viable treatment for patients with B-cell malignancies, might fill that unmet need for those who exhibit intolerance to ibrutinib or acalabrutinib. FUNDING: BeiGene.

Chemotherapeutic strategies in advanced or metastatic pancreatic adenocarcinoma.

Pancreatic cancer remains a formidable challenge for oncologists. The only curative option remains surgical resection in early-staged disease. Cytotoxic chemotherapy offers a modest survival benefit in the advanced or metastatic stage. Clinical trials of therapy have not yet yielded encouraging outcomes in advanced pancreatic cancer. In this review, we highlight recent developments in therapy focusing on trials conducted in the advanced or metastatic setting and offer insight into the challenges for future studies.

Pleiotropic effects of genistein in metabolic, inflammatory, and malignant diseases.

Genistein is a soy-derived biologically active isoflavone that exhibits diverse health-promoting effects. An increasing body of evidence shows that genistein influences lipid homeostasis and insulin resistance, counteracts inflammatory cytokines, and possesses antidiabetic properties. Genistein also impedes cancer progression by promoting apoptosis, inducing cell cycle arrest, modulating intracellular signaling pathways, and inhibiting angiogenesis and metastasis of neoplastic cells. This review summarizes the pleiotropic functions of genistein in common health disorders such as metabolic syndrome, chronic inflammatory diseases, and cancer. In the current era of uncontrolled health expenditure, a focus on the clinical development of nutritional agents with the capacity to prevent a variety of common health disorders is needed. As a micronutrient that exerts multifaceted effects ranging from antidiabetic to anticarcinogenic functions, genistein should be clinically developed further for use in the prevention and treatment of a variety of health disorders.

Risk factors for rising incidence of esophageal and gastric cardia adenocarcinoma.

INTRODUCTION: In the last 30 years, the incidence of esophageal and gastric cardia adenocarcinoma has steadily increased. The increase in incidence is approximately seven-fold, which is a more substantial increase than that of several malignancies, including melanoma, breast cancer, and prostate cancer. DISCUSSION: The rising incidence has led to a steady increase in mortality from 2 to 15 deaths per 100,000 in the last three decades. The etiologic factors involved in the development of these malignancies include gastroesophageal reflux disease, Barrett's esophagus, acid-suppressive medication use, obesity, and tobacco use. This article discusses the contribution of these etiologic risk factors to this increase in incidence.

The impact of curcumin on breast cancer.

Curcumin, the active ingredient of turmeric (curry spice), is believed to be associated with reducing the incidence of breast cancers in Asian countries. Anti-cancer efficacy of curcumin and analogs has been tested in pre-clinical studies in some cancer models including breast cancer. These studies reported promising results in inhibiting human cancer cell proliferation and tumorigenesis in animal models. Both in vitro and in vivo studies have shown that curcumin and its analogs target critical genes associated with angiogenesis, apoptosis, cell cycle, and metastasis. The inhibition of human breast cancer cell growth by curcumin is mediated via certain signaling cascades including the modulation of the NF-κB signaling pathway. Epidemiological and experimental data also demonstrated the efficacy of curcumin in chemoprevention and reversing chemo-resistance of tumors of certain cancers. This review summarizes the studies revealing the preventive and therapeutic effects of curcumin and its analogs with an emphasis on multi-targeted biological and molecular effects in a breast cancer model.

Developing histone deacetylase inhibitors in the therapeutic armamentarium of pancreatic adenocarcinoma.

INTRODUCTION: Histone deacetylases (HDACs) are commonly dysregulated in pancreatic adenocarcinoma (PA) and have a central role in the development and progression of the disease. HDAC is a family of enzymes involved in deacetylation of lysine residues on histone and non-histone proteins. Deacetylation of histone proteins leads to compaction of the DNA/histone complex resulting in inhibition of gene expression. Deacetylation of non-histone proteins can affect the stability and function of key proteins leading to dysregulation of cellular signaling pathways. HDAC inhibitors have been shown to potentiate the antiproliferative and proapoptotic effects of several cytotoxic agents, in vitro and in vivo PA xenograft models. AREAS COVERED: The areas covered include the biology and function of the HDAC isoenzymes and their significant role in multiple oncogenic pathways in PA. Preclinical and clinical trials evaluating HDAC inhibitors are also reviewed. EXPERT OPINION: Despite discouraging early phase clinical trials evaluating HDAC inhibitors in PA, this strategy deserves further evaluation guided by better preclinical studies in identifying the role of specific HDAC isoenzyme inhibitors in PA. Evaluation of the effects of HDAC inhibitors on PA stem cell function and epithelial to mesenchymal transformation is also an evolving area that holds future potential for these agents. Such preclinical studies will yield insight into the functionality of HDAC isoenzymes, which can then be translated into rationally designed clinical trials. One such strategy could focus on HDAC inhibition employed in combination with proteasome inhibition targeting the aggresome pathway in PA.

Participation and survival of geriatric patients in Phase I clinical trials: the Karmanos Cancer Institute (KCI) experience.

BACKGROUND: Geriatric cancer patients (age 65 or older) comprise a majority of cancer cases in the United States, yet they are underrepresented in therapeutic clinical trials. It is therefore important to increase our understanding of their participation, survival outcomes, and recruitment barriers. This study aims to describe the demographics, treatment, toxicity, and overall survival (OS) of all patients ≥ 65 years of age who presented to the Phase I Clinical Trials service at Karmanos Cancer Institute (KCI). METHODS: A retrospective chart review was performed of all referred and seen patients ≥ 65 years of age at Phase I clinical service at KCI between 1995-2005. Data on demographics, co-morbidities, tumor type, reason not enrolled, toxicities and OS were obtained. RESULTS: A total of 216 patients met the study criteria. The median age was 71 years. 114 (59%) patients were performance status 1. 102 (47%) patients were enrolled and of those 95 (44%) patients were treated. More than half of the patients failed to enroll with predominant reasons being protocol ineligibility (30%), loss to follow up (12%), patient refusal (8%), or unavailability of trial (2%). The median OS duration of treated patients was 8.4 months (95% CI: 6.2-10.5). This was significantly longer than the patients who failed to enroll or did not receive treatment (p < 0.0001). CONCLUSION: This study suggests that elderly patients who were treated on a Phase I clinical trial(s) at our institution survived significantly longer than our elderly patients who did not receive treatment.

Apocrine carcinoma of the face in a 62-year-old Asian man.

Apocrine carcinoma (AC) is a rare tumor with heterogeneous presentation. The disease has a highly morbid course and little is known about it. We present an otherwise healthy, 62-year-old Asian male who originally presented with chronic swelling of his left eyelid associated with excessive tears and diminished vision was diagnosed with AC. AC is often challenging to diagnose, yet it is critical to do so as early diagnosis and treatment can maximize patient survival.

PAR-4 as a possible new target for pancreatic cancer therapy.

IMPORTANCE OF THE FIELD: Pancreatic cancer (PC) is a deadly disease that is intractable to currently available treatment regimens. Although well described in different tumors types, the importance of apoptosis inducer prostate apoptosis response-4 (Par-4) in PC has not been appreciated. PC is an oncogenic kras driven disease, which is known to downregulate Par-4. Therefore, this review highlights its significance and builds a strong case supporting the role of Par-4 as a possible therapeutic target in PC. AREAS COVERED IN THIS REVIEW: Literature-based evidence spanning the last 15 years on Par-4 and its significance in PC. WHAT THE READER WILL GAIN: This review provides comprehensive knowledge of the significance of Par-4 and its association with kras status in PC, along with the crosstalk with crucial resistance and survival molecules NF-kappaB and Bcl-2 that ultimately are responsible for the overall poor outcome of different therapeutic approaches in this disease. TAKE HOME MESSAGE: Par-4 holds promise as a potential therapeutic target that can be induced by chemopreventive agents and small-molecule inhibitors either alone or in combination with standard chemotherapeutics leading to selective apoptosis in PC cells. It also acts as a chemosensitizer and therefore warrants further clinical investigations in this disease.

Reactivation of p53 by novel MDM2 inhibitors: implications for pancreatic cancer therapy.

The present study is the first to show in pancreatic cancer (PC) the growth inhibition and apoptosis by novel MDM2 inhibitors (MI-319 & 219) through reactivation of p53 pathway. Our results highlight two new secondary targets of MDM2 inhibitor 'SIRT1' and Ku70. SIRT1 which has a role in ageing and cancer and is known to regulate p53 signaling through acetylation. Ku70 is a key component of non-homologous end joining machinery in the DNA damage pathway and is known to regulate apoptosis by blocking Bax entry into mitochondria. Growth inhibition and apoptosis by MI-219, MI-319 was accompanied by increase in levels of p53 along with p21(WAF1) and the proapoptotic Puma. SiRNA against p21(WAF1) abrogated the growth inhibition of PC cells confirming p21(WAF1) as a key player downstream of activated p53. Immunoprecipitation-western blot analysis revealed reduced association of MDM2-p53 interaction in drug exposed PC cells. In combination studies, the inhibitors synergistically augmented anti-tumor effects of therapeutic drug gemcitabine both in terms of cell growth inhibition as well as apoptosis. Surface plasmon resonance studies confirmed strong binding between MI-319 and Ku70 (K(D) 170 nM). Western blot revealed suppression of SIRT1 and Ku70 with simultaneous upregulation of acetyl-p53 (Lys379) and Bax. Co-Immunoprecipitation studies confirmed that MI-319 could disrupt Ku70-Bax and SIRT1-Bax interaction. Further, using wt-p53 xenograft of Capan-2, we found that oral administration of MI-319 at 300 mg/kg for 14 days resulted in significant tumor growth inhibition without any observed toxicity to the animals. No tumor inhibition was found in mut-p53 BxPC-3 xenografts. In light of our results, the inhibitors of MDM2 warrant clinical investigation as new agents for PC treatment.

Anemia and the potential role of erythropoiesis-stimulating agents in heart failure.

The recognition of the high prevalence and the independent prognostic role of anemia in heart failure (HF) has contributed to intensification of the search for an effective treatment. A central role of erythropoietin in cardiorenal anemia syndrome has been proposed. Several clinical trials have established the safety and efficacy of erythropoiesis-stimulating agents in correcting anemia in patients with HF. The recognition of the pleiotropic effect of erythropoietin has expanded targets of therapy. The ongoing outcomes trial with darbepoetin alfa will determine the role of this novel therapy in the treatment of HF.