Elena Ongaro

Clinical advances in the development of novel VEGFR2 inhibitors

Angiogenesis inhibitors have produced significant advances in the treatment of several tumors including colorectal, lung, ovarian and renal carcinomas. These agents, however, modestly impact on the overall cure rate, and their activity is often limited because of the early outbreak of redundant pathways or resistance mechanisms. Moreover, no clear predictive factor has been identified for treatment selection in the clinic. Preclinical evidence suggest that antibodies targeting the vascular endothelial growth factor (VEGF) axis may exert their activity throughout the inhibition of VEGF receptor 2 (VEGFR2) phosphorylation, a key factor in the cancer angiogenic process. Among other molecules, ramucirumab, an intravenously administered, fully humanized monoclonal antibody (mAb) targeting the extracellular domain of the receptor, and apatinib, a potent oral inhibitor of the intracellular domain, are emerging as original antiangiogenic opportunities. This up-to-date review focuses on the development of VEGFR2 inhibitors across multiple cancers and presents results of the most recent researches, ranging from early phase I studies to randomized phase III trials, in which those drugs have been tested as a single-agent or in combination with different chemotherapy regimens.

The challenge of targeted therapies for gastric cancer patients: the beginning of a long journey

Introduction: Despite significant improvements in systemic chemotherapy over the last two decades, the prognosis of patients with advanced disease remains dismal. Collaborative, high-quality research and advances in high-throughput technologies have contributed to elucidate molecular pathways underpinning disease progression and have stimulated many clinical studies testing target therapies in the advanced disease setting. Although progress has been made thanks to trastuzumab in HER2 positive tumours, antiangiogenic drugs have produced conflicting results and EGFR-inhibitors have failed to show major improvements. Areas covered: While commenting on the results of many key Phase III randomized trials, the Authors discuss the most promising classes of novel targeted agents and present the current challenges toward a customized treatment. Expert opinion: Palliative chemotherapy became the worldwide standard of care for patients with advanced gastric cancers, producing significant life prolongation and improvement of life quality. Nevertheless, long-term outcomes of those patients remain poor. Because of the encouraging advancement in novel targeted therapies, such a disappointing scenario is now evolving. While results serve as a springboard for future research, more comprehensive efforts are needed to clarify the biological mechanisms underpinning cancer progression and help clinicians to develop new effective treatments.

Immunotherapy for colorectal cancer: where are we heading?

ABSTRACT Introduction: In the last few years, significant advances in molecular biology have provided new therapeutic options for colorectal cancer (CRC). The development of new drugs that target the immune response to cancer cells seems very promising and has already been established for other tumor types. In particular, the use of immune checkpoint inhibitors seems to be an encouraging immunotherapeutic strategy. Areas covered: In this review, the authors provide an update of the current evidence related to this topic, though most immunotherapies are still in early-phase clinical trials for CRC. To understand the key role of immunotherapy in CRC, the authors discuss the delicate balance between immune-stimulating and immune-suppressive networks that occur in the tumor microenvironment. Expert opinion: Modulation of the immune system through checkpoint inhibition is an emerging approach in CRC therapy. Nevertheless, selection criteria that could enable the identification of patients who may benefit from these agents are necessary. Furthermore, potential prognostic and predictive immune biomarkers based on immune and molecular classifications have been proposed. As expected, additional studies are required to develop biomarkers, effective therapeutic strategies and novel combinations to overcome immune escape resistance and enhance effector response.

Angiogenic inhibitors in gastric cancers and gastroesophageal junction carcinomas: A critical insight

Advanced gastric cancer ranks second as the global leading cause of cancer-related death and improvements in systemic chemotherapy have reached a plateau. Advanced molecular sequencing techniques help identifying patients more likely to respond to targeted agents; nevertheless we are still far from major breakthroughs. Although antiangiogenic drugs have produced notable advances, redundant pathways or mechanisms of resistance may limit their efficacy. Novel compounds have been recently developed to specifically target VEGF receptors, PlGF, FGF, MET, and angiopoietin. Ramucirumab, a monoclonal antibody specifically directed against the VEGFR-2, has emerged as a novel therapeutic opportunity. REGARD and RAINBOW were the first phase III studies to report the value of this strategy in gastric cancer patients, and other ongoing trials are testing novel antiangiogenic compounds. The aim of our review is to present the state-of-the-art of novel antiangiogenic compounds in advanced gastric cancer, underlying the biology, their mechanism of action, and their clinical results.

Prognostic significance of K-Ras mutation rate in metastatic colorectal cancer patients

Introduction: Activating mutations of K-Ras gene have a well-established role as predictors of resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC) patients. Their prognostic value is controversial, and no data regarding the prognostic value of mutation rate, defined as the percentage of mutated alleles/tumor sample, are available. We aimed to evaluate the prognostic value of K-Rasmutation rate in a homogenous cohort of mCRC patients receiving first-line doublet plus bevacizumab. Patients and Methods: This retrospective study enrolled 397 K-Ras mutant mCRC patients from 6 Italian centers, and 263 patients were fully evaluable for our analysis. K-Ras mutation rate was assessed by pyrosequencing. Patients with less than 60% of cancer cells in tumor tissue were excluded. No patients received anti-EGFR containing anticancer therapy, at any time. Median mutation rate was 40% and was adopted as cut-off. The primary and secondary endpoints were PFS and OS respectively. Results: At univariate analysis, K-Ras mutation rate higher than 40% was significantly associated with lower PFS (7.3 vs 9.1 months; P < 0.0001) and OS (21 vs 31 months; P = 0.004). A multivariate model adjusted for age at diagnosis, site of origin of tumor tissue (primary vs metastases), referral center, number of metastatic sites, and first-line chemotherapy backbone, showed that K-Ras mutation rate remained a significant predictor of PFS and OS in the whole population. Discussion: Our data demonstrate an association between K-Ras mutation rate and prognosis in mCRC patients treated with bevacizumab-containing first-line therapy. These data deserve to be verified in an independent validation set.

Glycolysis gene expression analysis and selective metabolic advantage in the clinical progression of colorectal cancer

Production of lactate even in the presence of sufficient levels of oxygen (aerobic glycolysis) seems the prevalent energy metabolism pathway in cancer cells. The analysis of altered expression of effectors causing redirection of glucose metabolism would help to characterize this phenomenon with possible therapeutic implications. We analyzed mRNA expression of the key enzymes involved in aerobic glycolysis in normal mucosa (NM), primary tumor (PT) and liver metastasis (LM) of colorectal cancer (CRC) patients (pts) who underwent primary tumor surgery and liver metastasectomy. Tissues of 48 CRC pts were analyzed by RT-qPCR for mRNA expression of the following genes: hexokinase-1 (HK-1) and 2 (HK-2), embryonic pyruvate kinase (PKM-2), lactate dehydrogenase-A (LDH-A), glucose transporter-1 (GLUT-1), voltage-dependent anion-selective channel protein-1 (VDAC-1). Differences in the expression of the candidate genes between tissues and associations with clinical/pathologic features were studied. GLUT-1, LDH-A, HK-1, PKM-2 and VDAC-1 mRNA expression levels were significantly higher in PT/LM tissues compared with NM. There was a trend for higher expression of these genes in LM compared with PT tissues, but differences were statistically significant for LDH-A expression only. RAS mutation-positive disease was associated with high GLUT-1 mRNA expression levels only. Right-sided colon tumors showed significantly higher GLUT-1, PKM-2 and LDH-A mRNA expression levels. High glycolytic profile was significantly associated with poor prognosis in 20 metastatic, RAS-mutated pts treated with first-line chemotherapy plus Bevacizumab. Altered expression of effectors associated with upregulated glucose uptake and aerobic glycolysis occurs in CRC tissues. Additional analyses are warranted for addressing the role of these changes in anti-angiogenic resistance and for developing novel therapeutics.

HER2 loss in HER2-positive gastric or gastroesophageal cancer after trastuzumab therapy : Implication for further clinical research

Mechanisms of acquired resistance to trastuzumab‐based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post‐progression in patients receiving chemotherapy and trastuzumab for advanced HER2‐positive [immunohistochemistry (IHC) 3+ or 2+ with in‐situ hybridization (ISH) amplification] gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over‐expression were defined as post‐trastuzumab IHC score <3+ and absence of ISH amplification, and IHC “downscoring” from 2+/3+ to 0/1+, respectively. HER2 IHC was always performed, while ISH was missing in 3 post‐progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over‐expression was observed in 32 and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinicopathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80 vs. 14%; p = 0.008) and HER2 over‐expression (63 vs. 14%; p = 0.025). As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab‐based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti‐HER2 second‐line strategies in initially HER2‐positive disease.

Molecular classifications of gastric cancers: Novel insights and possible future applications

Despite some notable advances in the systemic management of gastric cancer (GC), the prognosis of patients with advanced disease remains overall poor and their chance of cure is anecdotic. In a molecularly selected population, a median overall survival of 13.8 mo has been reached with the use of human epidermal growth factor 2 (HER2) inhibitors in combination with chemotherapy, which has soon after become the standard of care for patients with HER2-overexpressing GC. Moreover, oncologists have recognized the clinical utility of conceiving cancers as a collection of different molecularly-driven entities rather than a single disease. Several molecular drivers have been identified as having crucial roles in other tumors and new molecular classifications have been recently proposed for gastric cancer as well. Not only these classifications allow the identification of different tumor subtypes with unique features, but also they serve as springboard for the development of different therapeutic strategies. Hopefully, the application of standard systemic chemotherapy, specific targeted agents, immunotherapy or even surgery in specific cancer subgroups will help maximizing treatment outcomes and will avoid treating patients with minimal chance to respond, therefore diluting the average benefit. In this review, we aim at elucidating the aspects of GC molecular subtypes, and the possible future applications of such molecular analyses.

Evidence-based appraisal of the upfront treatment for unresectable metastatic colorectal cancer patients.

Colorectal cancer (CRC) is a significant health problem, with around 1 million new cases and 500000 deaths every year worldwide. Over the last two decades, the use of novel therapies and more complex treatment strategies have contributed to progressively increase the median survival of patients with unresectable advanced CRC up to approximately 30 mo. The availability of additional therapeutic options, however, has created new challenges and generated more complicated treatment algorithms. Moreover, several clinically important points are still in debate in first-line, such as the optimal treatment intensity, the most appropriate maintenance strategy, the preferred biologic to be used upfront in patients with KRAS wild-type CRC, and the need for more detailed information on tumor biology. In this moving landscape, this review analyses why the first-line treatment decision is crucial and how the choice may impact on further treatment lines. In addition, it focuses on results of major phase III randomized trials.

HER-2 inhibition in gastric and colorectal cancers: Tangible achievements, novel acquisitions and future perspectives

HER-2 (ErbB-2, c-erbB2 or Her2/neu), a member of the HER-family, is directly involved in the pathogenesis and progression of several human cancers; as such, it is also often considered as a poor prognostic factor. Following the revolutionary impact of anti-HER-2 therapy in breast cancer patients, the role of HER-2 and its blockade has also been extensively evaluated in other tumor types, including gastric and colorectal adenocarcinoma. The aims of this review are to recall the important results achieved with the use of HER-2 inhibitors in both gastric and colorectal cancer, and to discuss on the updates available on the role of HER-2 as prognostic and predictive factor in these malignancies.