Drug development in pancreatic cancer

Pancreatic cancer is rarely curable, and only 5% of patients achieve long-term survival. The vast majority of patients present with metastatic or unresectable disease. Standard chemotherapy with gemcitabine provides clinical benefit to only a small minority of patients. Thus, the development and investigation of new therapies is clearly needed. As knowledge of the underlying biology of pancreatic cancer has increased, targeted therapies based upon preclinical laboratory work have been developed, and are entering clinical trials. Some of these agents lack traditional dose-limiting toxicities (DLTs) at biologically active doses, and therefore clinical evaluation may not follow traditional guidelines for cytotoxic drug development. This article focuses on targeted therapies currently undergoing clinical evaluation in pancreatic cancer. Classes of therapeutics reviewed include those targeting tumor-microenvironment interactions (matrix metalloproteinase inhibitors, vascular endothelial growth-factor blockade), signal transduction (e.g., farnesyltransferase inhibitors), growth-factor receptors (epidermal growth-factor receptor blockade, Her-2/neu, gastrin), and vaccine approaches. Currently, there is a renewed optimism that the clinical application of biologic understanding will lead to an improved outcome for patients with pancreatic cancer.     

Inflammation in the development of lung cancer: epidemiological evidence

The lung is a site for repeated or chronic inflammatory insults. Epidemiologic research has provided evidence to support the hypothesis that tissue damage caused by inflammation can initiate or promote the development of lung cancer, possibly in conjunction with tobacco use. For example, some studies suggest an increased risk of lung cancer among persons with lung infections, such as tuberculosis, bacterial pneumonia, or inflammatory lung diseases. Elevated serum levels of C-reactive protein, an inflammation marker, are associated with heightened lung cancer risk. Recent studies also demonstrate increased lung cancer risk among immunosuppressed individuals infected with HIV. Other research indicates an association between genetic polymorphisms in the inflammation pathway, which might modulate the inflammatory response and lung cancer risk.     

Inflammation marker and risk of pancreatic cancer: a nested case-control study within the EPIC cohort

Background:

Established risk factors for pancreatic cancer include smoking, long-standing diabetes, high body fatness, and chronic pancreatitis, all of which can be characterised by aspects of inflammatory processes. However, prospective studies investigating the relation between inflammatory markers and pancreatic cancer risk are scarce.

Methods:

We conducted a nested case–control study within the European Prospective Investigation into Cancer and Nutrition, measuring prediagnostic blood levels of C-reactive protein (CRP), interleukin-6 (IL-6), and soluble receptors of tumour necrosis factor-α (sTNF-R1, R2) in 455 pancreatic cancer cases and 455 matched controls. Odds ratios (ORs) were estimated using conditional logistic regression models.

Results:

None of the inflammatory markers were significantly associated with risk of pancreatic cancer overall, although a borderline significant association was observed for higher circulating sTNF-R2 (crude OR=1.52 (95% confidence interval (CI) 0.97–2.39), highest vs lowest quartile). In women, however, higher sTNF-R1 levels were significantly associated with risk of pancreatic cancer (crude OR=1.97 (95% CI 1.02–3.79)). For sTNF-R2, risk associations seemed to be stronger for diabetic individuals and those with a higher BMI.

Conclusion:

Prospectively, CRP and IL-6 do not seem to have a role in our study with respect to risk of pancreatic cancer, whereas sTNF-R1 seemed to be a risk factor in women and sTNF-R2 might be a mediator in the risk relationship between overweight and diabetes with pancreatic cancer. Further large prospective studies are needed to clarify the role of proinflammatory proteins and cytokines in the pathogenesis of exocrine pancreatic cancer.     

Helicobacter pylori infection and development of pancreatic cancer.

BACKGROUND: Infection with Helicobacter pylori is an established risk factor for gastric cancer. Results from two studies suggest that it may also be a risk factor for pancreatic cancer. METHODS: We conducted a nested case control study among 128,992 adult subscribers to the Kaiser Permanente Medical Care Program who had been enrolled in a multiphasic health checkup from 1964 to 1969. Serum collected during the checkup was maintained frozen, and subjects were followed for cancer. Cases consisted of 104 randomly selected subjects among 507 who developed pancreatic cancer in the cohort. Controls consisted of 262 pancreatic cancer-free subjects from a pool of 730 controls previously tested for studies conducted on this cohort. Controls were individually matched to cases on age, gender, race, site, and date of multiphasic health checkup. Control sera were compared with cases for antibodies to H. pylori and the CagA protein. The effects of smoking, alcohol consumption, obesity, and years of education were also investigated. RESULTS: Neither H. pylori [odds ratio (OR), 0.85; 95% confidence interval (95% CI), 0.49-1.48] nor its CagA protein (OR, 0.96; 95% CI, 0.48-1.92) was associated with subsequent development of pancreatic cancer. Smoking (OR, 2.09; 95% CI, 1.17-3.74) and greater number of years of education (OR, 2.13; 95% CI, 1.23-3.69) were risk factors for pancreatic cancer, whereas alcohol consumption and obesity were not. CONCLUSION: Our results suggest that H. pylori infection is not associated with development of pancreatic cancer.     

Effects of melphalan on the development of experimental pancreatic cancer

The effects of melphalan were studied in rats fed raw soya flour and injected with azaserine in order to determine the suitability of this experimental model for testing drugs potentially useful for the treatment of pancreatic cancer. While melphalan did not prevent or delay the development of pancreatic cancer in these rats, the drug significantly lessened the number and size of the premalignant proliferative lesions in the pancreas. It seems that the model is useful both for testing potentially useful therapeutic agents and for analysing some of the processes involved in the development of pancreatic cancer.     

Inflammation and prostate cancer

Prostate cancer remains a major health concern for the male population throughout the Western world. It is today widely accepted that inflammation has a role in many human cancers. In fact, inflammation is thought to incite carcinogenesis by causing cell and genome damage, promoting cellular turnover and creating a tissue microenvironment that can enhance cell replication, angiogenesis and tissue repair. Accordingly, there is a body of literature suggesting a link between chronic inflammation and prostate cancer, in which prostate inflammation may contribute to the promotion of prostate cancer development. On the other hand, high levels of endogenous gonadal steroids are considered as risk factors for prostate cancer. Interestingly, it is clear that elevation of estrogens in the presence of testosterone results in a prostate-specific inflammatory response. Thus, it is possible that early inflammatory events stimulated by sex hormones serve as a prerequisite for the onset of prostate cancer.     

Future directions in drug development in pancreatic cancer

Pancreatic cancer is still one of the most lethal cancers with a reported 5-year relative survival rate of approximatively 9% and medical treatment remains a major challenge. Systemic treatment is recommended in every setting: resectable, borderline resectable, locally advanced and metastatic. Yet, few groundbreaking changes in practice have occurred in the last 30 years compared to other cancers and new treatments options are highly desirable. Most treatment approaches using chemotherapy have failed to improve patients' life expectancy and the few therapies finally found to have statistically significant benefit actually have modest clinical impact. It is becoming imperative to find new paths for improvement, such as encapsulated agents, new generation targeted therapies and treatments directed against the tumor microenvironment. We report here the new drugs of interest in pancreatic cancer and analyze the most recent failures.     

Growth of pancreatic foci and development of pancreatic cancer with a single dose of azaserine in the rat

Studies were undertaken to characterize the growth of the azaserine-inducedputative preneoplastic lesions in rats and to determine if asingle dose of azaserine would be carcinogenic. Male Lewis ratswere given a single i.p. injection of 30 mg L-azaserine/kg bodyweight at 7 weeks of age. A purified diet was fed throughoutthe study. Rats (10–12 per group) were autopsied at 6,9, 12, 15 and 18 months postinitiation, and pancreases werequantitatively evaluated to characterize the growth of acidophilicand basophilic foci and nodules (henceforth called foci), andthe incidence of neoplasms. All azaserine-treated rats had foci,and at all times approximately equal numbers of acidophilicand basophilic foci were present in the pancreas. The numberof basophilic foci increased with time, and while their sizealso increased, this change was small compared with the increasein size of the acidophilic foci. Conversely, all acidophillcfoci appeared to be present by 6–9 months, and their sizegreatly increased with time. The data suggest that virtuallyall foci persist rather than regress or remodel. At 9 monthsthe incidence of carcinoma in situ was 30% and by 18 monthsthere was a 100% incidence of pancreatic cancers (58% carcinomain situ and 42% carcinoma).     

Streptozotocin prevents development of nitrosamine-induced pancreatic cancer in the Syrian hamster

Administration of the nitrosamine carcinogen N-nitroso-bis (2-oxopropyl) amine (BOP) by subcutaneous injection (5 mg/kg/week) led to the development of invasive pancreatic ductular adenocarcinoma in 100% of normal Syrian hamsters by 24 weeks. Pretreatment of a second group of hamsters with the beta-cell toxin streptozotocin in a diabetogenic dose (50 mg/kg i.p. X 3) completely prevented the development of pancreatic cancer when BOP was subsequently administered. The mechanism of blockade by streptozotocin is unknown. This study suggests the potential importance of the endocrine pancreas in exocrine pancreatic carcinogenesis.     

Inflammation and cancer: the oncogene-driven connection

Inflammation has long been suspected to contribute to tumor growth. However, the concept that oncogenes, known for decades as responsible for cell neoplastic transformation, build up an inflammatory pro-tumorigenic microenvironment is emerging only in the last few years. The well known oncogenes RAS and MYC have been causally linked to tumor angiogenesis through different ways. Moreover, in thyroid tumors, where many of the genetic tumor-initiating events have been identified, the oncogenes driving tumorigenesis were proved able to induce an inflammatory program. This minireview will focus on growing evidence implicating the role of intrinsic, oncogene-driven pathways leading to pro-tumoral inflammation.     

Targeting reactive oxygen species in development and progression of pancreatic cancer

Introduction: Pancreatic ductal adenocarcinoma (PDA) is characterized by expression of oncogenic KRas which drives all aspects of tumorigenesis. Oncogenic KRas induces the formation of reactive oxygen species (ROS) which have been implicated in initiation and progression of PDA. To facilitate tumor promoting levels and to avoid oncogene-induced senescence or cytotoxicity, ROS homeostasis in PDA cells is balanced by additional up-regulation of antioxidant systems.

Areas covered: We examine the sources of ROS in PDA, the mechanisms by which ROS homeostasis is maintained, and the biological consequences of ROS in PDA. Additionally, we discuss the potential mechanisms for targeting ROS homoeostasis as a point of therapeutic intervention. An extensive review of the relevant literature as it relates to the topic was conducted using PubMed.

Expert commentary: Even though oncogenic mutations in the KRAS gene have been detected in over 95% of human pancreatic adenocarcinoma, targeting its gene product, KRas, has been difficult. The dependency of PDA cells on balancing ROS homeostasis could be an angle for new prevention or treatment strategies. These include use of antioxidants to prevent formation or progression of precancerous lesions, or methods to increase ROS in tumor cells to toxic levels.     

Inflammation, proteases and cancer

Tumours are complex tissues composed of ever-evolving neoplastic cells, matrix proteins that provide structural support and sequester biologically active molecules, and a cellular stromal component. Reciprocal interactions between neoplastic cells, activated host cells and the dynamic micro-environment in which they live enables tumour growth and dissemination. It has become evident that early and persistent inflammatory responses observed in or around developing neoplasms regulates many aspects of tumour development (matrix remodelling, angiogenesis, malignant potential) by providing diverse mediators implicated in maintaining tissue homeostasis, e.g., soluble growth and survival factors, matrix remodelling enzymes, reactive oxygen species and other bioactive molecules. This review highlights recent insights into the role of chronic inflammation associated with cancer development and examines proteolytic pathways activated by infiltrating leukocytes during neoplastic programming of tissues.     

Inflammation and cancer stem cells

Cancer stem cells are becoming recognised as being responsible for metastasis and treatment resistance. The complex cellular and molecular network that regulates cancer stem cells and the role that inflammation plays in cancer progression are slowly being elucidated. Cytokines, secreted by tumour associated immune cells, activate the necessary pathways required by cancer stem cells to facilitate cancer stem cells progressing through the epithelial–mesenchymal transition and migrating to distant sites. Once in situ, these cancer stem cells can secrete their own attractants, thus providing an environment whereby these cells can continue to propagate the tumour in a secondary niche.     

Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer

Background:

The purpose of this work was to determine the efficacy of inhibiting mammalian target of rapamycin (mTOR) in pancreatic cancer preclinical models and translate preclinical observations to the clinic.

Methods:

Temsirolimus (20 mg Kg⁻¹ daily) was administered to freshly generated pancreatic cancer xenografts. Tumour growth inhibition was determined after 28 days. Xenografts were characterised at baseline by gene expression and comparative genomic hybridisation. Patients with advanced, gemcitabine-resistant pancreatic cancer were treated with sirolimus (5 mg daily). The primary end point was 6-month survival rate (6mSR). Correlative studies included immunohistochemistry assessment of pathway expression in baseline tumours, drug pharmacokinetics (PKs), response assessment by FDG-PET and pharmacodynamic effects in peripheral-blood mononuclear cells (PBMCs).

Results:

In all, 4 of 17 xenografts (23%) responded to treatment. Sensitive tumours were characterised by gene copy number variations and overexpression of genes leading to activation of the PI3K/Akt/mTOR pathway. Activation of p70S6K correlated with drug activity in the preclinical studies. Sirolimus was well tolerated in the clinic, showed predictable PKs, exerted pathway inhibition in post-treatment PBMCs and resulted in a 6mSR of 26%. No correlation, however, was found between activated p70S6K in tumour tissues and anti-tumour effects.

Conclusion:

Sirolimus activity in pancreatic cancer was marginal and not predicted by the selected biomarker.     

lncRNA/miRNA在胰腺癌发生发展中的研究进展

ncRNA/miRNA在多种实体肿瘤中表达异常,参与肿瘤的增殖、侵袭、转移。胰腺癌是发病率较高、死亡率高的恶性肿瘤,通过深入研究lncRNA/miRNA在胰腺癌发生发展中的分子机制,可为胰腺癌的治疗提供新的靶点。