Andreas Pircher

Targeting the insulin-like growth factor network in cancer therapy

During the last decades, changes in the insulin-like growth factor (IGF) signaling have been related to the pathogenesis of cancer. Therefore, IGFs became highly attractive therapeutic cancer targets. Several drugs including monoclonal antibodies (mAB), small molecule tyrosine kinase inhibitors (RTKIs), anti-sense oligonucleotids (ASOs) and IGF-binding proteins (IGFBPs) targeting the IGF axis were developed. With over 60 ongoing clinical trials, the IGF1 receptor (IGF1R) is currently one of the most studied molecular targets in the field of oncology. In this review, we provide an overview on the IGF axis, its signaling pathways and its significance in neoplasia. We critically review the preclinical and clinical studies investigating the role of IGF1R as a cancer target and discuss preliminary results and possible limitations.

Endothelial progenitor cells: current issues on characterization and challenging clinical applications.

Since their discovery about a decade ago, endothelial precursor cells (EPC) have been subjected to intensive investigation. The vision to stimulate respectively suppress a key player of vasculogenesis opened a plethora of clinical applications. However, as research opened deeper insights into EPC biology, the enthusiasm of the pioneer era has been damped in favour of a more critical view. Recent research is focused on three major questions: The fact that the number of EPC in peripheral blood is exceedingly low has consistently raised suspicion whether these cells can plausibly have an impact on physiological or pathophysiological processes. Secondly, whereas the key role of EPC in tumourigenesis has been strongly emphasized by various groups in the past, recent publications are challenging this hypothesis. Thirdly, the lack of consensus on EPC-defining markers and standardized protocols for their detection have repeatedly led to difficulties concerning comparability between papers. In this current review, an overview on recent findings on EPC biology is given, their challenging clinical implications are discussed and the perplexity underlying the current controversial debate is illustrated.

Liver cancer: Targeted future options

Hepatocellular carcinoma (HCC) has a poor prognosis and systemic chemotherapies have disappointing results. The increasing knowledge of the molecular biology of HCC has resulted in novel targets, with the vascular endothelial growth factor and epidermal growth factor receptor (EGFR)-related pathways being of special interest. New blood vessel formation (angiogenesis) is essential for the growth of solid tumors. Anti-angiogenic strategies have become an important therapeutic modality for solid tumors. Several agents targeting angiogenesis-related pathways have entered clinical trials or have been already approved for the treatment of solid tumors. These include monoclonal antibodies, receptor tyrosine kinase inhibitors and immunomodulatory drugs. HCC is a highly vascular tumor, and angiogenesis is believed to play an important role in its development and progression. This review summarizes recent advances in the basic understanding of the role of angiogenesis in HCC as well as clinical trials with novel therapeutic approaches targeting angiogenesis and EGFR-related pathways.

Biomarkers in tumor angiogenesis and anti-angiogenic therapy.

Tumor angiogenesis has been identified to play a critical role in tumor growth and tumor progression, and is regulated by a balance of angiogenic and anti-angiogenic cytokines. Among them VEGF (vascular endothelial growth factor) and its signaling through its receptors are of crucial relevance. Inhibition of VEGF signaling by monoclonal antibodies or small molecules (kinase inhibitors) has already been successfully established for the treatment of different cancer entities and multiple new drugs are being tested in clinical trials. However not all patients are likely to respond to these therapies, but to date there are no reliable biomarkers available to predict therapy response. Many studies integrated biomarker programs in their study protocols, thus several potential biomarkers have been identified which are currently under clinical investigation in prospective randomized studies. This review intends to give an overview of the described potential biomarkers as well as different imaging techniques such as ultrasound and magnetic resonance imaging that can indicate benefit, resistance and toxicity to anti-angiogenic therapies.

Novel therapeutic approaches for the treatment of castration-resistant prostate cancer

Highlights • New drugs approved for treatment of castration resistant prostate cancer.• Prime targets: androgen receptor, bone cells, cell division, immune system.• Several promising drugs disappointed in clinical trials.• Further efforts necessary to optimize the sequence and combinations of drugs.• New biomarkers required for stratification of patient and therapy selection.

Treg(s) in Cancer: Friends or Foe?

Immune escape is a hallmark of cancer. Regulatory T cells (Treg) have been described to maintain peripheral tolerance. The role of Treg in cancer is ambiguous, as they are central inhibitory regulators in solid tumors, whereas during inflammation‐driven tumorigenesis they prevent cancer initiation by restraining inflammation. As a consequence, under conditions with chronic inflammation that may initiate malignant transformation, application rather than depletion of Treg may be helpful. In solid tumors, however, the success story of immune‐activating antibodies targeting checkpoint molecules of T cell activation fuels the hope that Treg inactivation or depletion may additionally boost anti‐tumor immune response. In this review we summarize important aspects on the dual role of Treg in cancer to provide a rationale for future Treg targeting attempts. J. Cell. Physiol. 9999: 2598–2605, 2015.

BRAF inhibition in hairy cell leukemia with low-dose vemurafenib.

The activating mutation of the BRAF serine/threonine protein kinase (BRAF V600E) is the key driver mutation in hairy cell leukemia (HCL), suggesting opportunities for therapeutic targeting. We analyzed the course of 21 HCL patients treated with vemurafenib outside of trials with individual dosing regimens (240-1920 mg/d; median treatment duration, 90 days). Vemurafenib treatment improved blood counts in all patients, with platelets, neutrophils, and hemoglobin recovering within 28, 43, and 55 days (median), respectively. Complete remission was achieved in 40% (6/15 of evaluable patients) and median event-free survival was 17 months. Response rate and kinetics of response were independent of vemurafenib dosing. Retreatment with vemurafenib led to similar response patterns (n = 6). Pharmacodynamic analysis of BRAF V600E downstream targets showed that vemurafenib (480 mg/d) completely abrogated extracellular signal-regulated kinase phosphorylation of hairy cells in vivo. Typical side effects also occurred at low dosing regimens. We observed the development of acute myeloid lymphoma (AML) subtype M6 in 1 patient, and the course suggested disease acceleration triggered by vemurafenib. The phosphatidylinositol 3-kinase hotspot mutation (E545K) was identified in the AML clone, providing a potential novel mechanism for paradoxical BRAF activation. These data provide proof of dependence of HCL on active BRAF signaling. We provide evidence that antitumor and side effects are observed with 480 mg vemurafenib, suggesting that dosing regimens in BRAF-driven cancers could warrant reassessment in trials with implications for cost of cancer care.

Neoadjuvant chemo-immunotherapy modifies CD4(+)CD25(+) regulatory T cells (Treg) in non-small cell lung cancer (NSCLC) patients.

BACKGROUND Regulatory T cells (Treg) are critical for cancer immune evasion; whereas natural killer (NK) cells are central for effective anti-tumor immunity including antibody-induced cellular cytotoxicity (ADCC). The predictive role of Treg levels for clinical response to chemo-immunotherapy in non-small cell lung cancer (NSCLC) as well as therapy-induced Treg changes remain to be defined. PATIENTS AND METHODS The impact of Treg on NK-mediated cetuximab-dependent cellular cytoxicity was tested in vitro. Frequency and functional activity of Treg was analyzed in 31 NSCLC stage IB-IIIA patients treated by neoadjuvant Cetuximab/Docetaxel/Cisplatin prior to surgery. Data were correlated with clinical outcome variables and Treg tumor infiltration. RESULTS Treg potently inhibit NK-mediated and cetuximab-induced ADCC in vitro. In addition, a significant correlation between Treg reduction and clinical response was seen. However, the grade of tumor infiltrating Treg in resected tumors did not correlate with peripheral Treg levels. Moreover, Treg levels at diagnosis did not predict clinical response to chemo-immunotherapy. CONCLUSIONS The drop of Treg levels during neoadjuvant chemo-immunotherapy in NSCLC patients significantly correlates with clinical response. However, Treg at diagnosis are not linked to inferior clinical response to chemo-immunotherapy in NSCLC in vivo even though Treg efficiently inhibit ADCC in vitro.

High Risk of Under-Grading and -Staging in Prostate Cancer Patients Eligible for Active Surveillance

Background Active surveillance (AS) is increasingly offered to patients with low risk prostate cancer. The present study was conducted to evaluate the risk of tumor under-grading and -staging for AS eligibility. Moreover, we analyzed possible biomarkers for predicting more unfavorable final tumor histology. Methods 197 patients who underwent radical prostatectomy (RPE) but would have met the EAU (European Association of Urology) criteria for AS (PSA<10 ng/ml, biopsy GS ≤6, ≤2 cancer-positive biopsy cores with ≤50% of tumor in any core and clinical stage ≤T2a) were included in the study. These AS inclusion parameters were correlated to the final histology of the RPE specimens. The impact of preoperative PSA level (low PSA ≤4 ng/ml vs. intermediate PSA of >4–10 ng/ml), PSA density (<15 vs. ≥ 15 ng/ml) and the number of positive biopsy cores (1 vs. 2 positive cores) on predicting upgrading and final adverse histology of the RPE specimens was analyzed in uni- and multivariate analyses. Moreover, clinical courses of undergraded patients were assessed. Results In our patient cohort 41.1% were found under-graded in the biopsy (final histology 40.1% GS7, 1% GS8). Preoperative PSA levels, PSA density or the number of positive cores were not predictive for worse final pathological findings including GS >6, extraprostatic extension and positive resection margin (R1) or correlated significantly with up-grading and/or extraprostatic extension in a multivariate model. Only R1 resections were predictable by combining intermediate PSA levels with two positive biopsy cores (p = 0.004). Sub-analyses showed that the number of biopsy cores (10 vs. 15 biopsy cores) had no influence on above mentioned results on predicting biopsy undergrading. Clinical courses of patients showed that 19.9% of patients had a biochemical relapse after RPE, among all of them were undergraded in the initial biopsy. Conclusion In summary, this study shows that a multitude of patients fulfilling the criteria for AS are under-diagnosed. The use of preoperative PSA levels, PSA density and the number of positive cores were not predictable for undergrading in the present patient collective.

Small steps of improvement in small-cell lung cancer (SCLC) within two decades: A comprehensive analysis of 484 patients

BACKGROUND It is not clear whether or not the fate of patients suffering from small-cell lung cancer (SCLC) has improved. To better understand the course of disease, we aimed at documenting disease features at initial diagnosis, sequences of therapy modalities and outcome in consecutive patients over two decades. We postulated that SCLC patients might have benefitted from refined diagnosis and treatment options during the last decade. METHODS All SCLC cases diagnosed at the Innsbruck University Hospital and associated institutions between 1991 and 2011 have been documented in detail in accordance with a prespecified protocol. RESULTS A total of 484 patients diagnosed with SCLC were followed. The most important symptoms at initial diagnosis were cough, dyspnea and tumor pain in 55%, 51% and 44%, respectively. Patients who were operated during early stage of disease (n = 26) had a favorable 5-year, relapse-free survival (74%). A total of 112 patients with locally advanced disease were treated by radiochemotherapy in curative intent (RCT), and achievement of CR offered a chance of long term overall survival (OS), reaching 44% after 10-years. In the palliative setting (median OS in 304 evaluable patients, 9.7 months), a therapeutic progress in the more recent decade could not be observed. Parameters independently associated with favorable OS were: response to therapy and prophylactic brain irradiation in patients with RCT; and response, age < 70 years and absence of LDH elevation in the palliative setting. CONCLUSIONS In this comprehensive view on SCLC, the findings on symptomatology, comorbidity, and spectrum of treatments may help to better understand individual courses of the disease. Overall, modern medicine failed to translate into substantial benefit of SCLC patients, except in patients in locally advanced disease receiving multimodal therapy.