Treatment Strategies In Oncology Research Articles

Predictive Pathology in the Target Therapy Era in Breast Cancer

Abstract The concept of precision medicine, where therapy is personalized to unique disease and host characteristics, is currently revolutionizing treatment strategies in oncology. A key point in this concept is the fact that several so-called targeted drugs may only be effective when tumors exhibit characteristic molecular features. This implies that companion diagnostic tests should be performed before treatment. There is evidence suggesting that the first step in predictive pathology is represented by morphology. For instance, histological types, such as tubular and cribriform carcinomas, define patients who may not need any treatments other than surgical excision. Neoadjuvant studies have shown that patients affected by lobular carcinomas are not likely to have any beneficial effects from chemotherapy. The second step in prediction is represented by immunophenotyping. If the immunohistochemical evaluation of four markers (estrogen and progesterone receptors, HER2 and Ki67) remains the best practice for breast cancer predictive pathology, molecular pathology has certainly reshaped the way we approach breast cancer diagnosis. The aim of this review is to discuss current knowledge in predictive pathology for the management of breast cancer patients, focusing on the benefits and drawbacks of traditional tools and of novel improvements of molecular biology.

Development of next generation antibody-based immunotherapy for childhood cancer neuroblastoma

BackgroundHigh risk neuroblastoma poses a significant clinical problem in paediatric oncology and new treatment strategies are needed. Antibody therapy specific for neuroblastoma surface molecule GD2 has been shown to improve outcome. Here we develop a new generation antibody-based therapeutic agent named BiTE (Bi-specific T cell Engager) that combines antibody specificity with potent T cell functions. MethodsTo identify the BiTE format with maximum activity against neuroblastoma, BiTEs were constructed with single chain variable fragments (scFv) derived from three different CD3-specific antibodies, scFv from two different GD2-specific antibodies, and three different flexible linkers between these CD3 (ie, T cell) and GD2 (ie, neuroblastoma) binders. Specific binding to CD3-positive and GD2-positive cell lines and cytolytic activity at a range of BiTE concentrations was assessed. FindingsSeven different BiTE formats have been successfully produced and purified. Whereas all seven BiTEs constructed showed binding to GD2-positive and CD3-positive cell lines and absence of binding to target antigen-negative cells, mean fluorescence intensity of CD3 binding (14·6 arbitrary units, 24·6, 255) and of GD2 binding (1366, 4258) indicated a range of affinities for CD3 and GD2. For each BiTE, lysis of GD2-target cells was only observed in the presence of T cells. Similarly, secretion of interferon γ by activated T cells only occurred in a CD3-specific and GD2-specific manner. All seven BiTEs induced GD2-specific cytolytic activity. Cytolytic activity was achieved at the lowest EC50 (ie, <1 ng/mL BiTE) for the BiTE format with highest GD2 affinity and moderate CD3 affinity. InterpretationOur findings demonstrate that the optimum BiTE design for tumour targeting can be identified by functional testing of BiTE formats incorporating CD3-specific scFvs and tumour antigen-specific scFvs with a range of binding affinities. Our optimum BiTE construct shows remarkable in-vitro activity approaching that of blinatumomab, which has proven clinical activity against leukaemia; we aim to develop this BiTE into a new therapeutic agent for neuroblastoma. FundingGreat Ormond Street Hospital Institute of Child Health Biomedical Research Centre, Wellcome Trust.

Current variations in childhood cancer supportive care in the Netherlands.

Current treatment strategies in pediatric oncology are intensive and lead to high survival rates but also to treatment-related complications. Therefore, supportive care plays an increasingly important role. This study was designed to evaluate variations in supportive care practice in children with cancer in the Netherlands and adherence to selected existing international guidelines through an in-depth review of local guidelines and protocols at all 6 Dutch pediatric cancer centers. Based on shared expert opinion, a questionnaire regarding current supportive care practice was compiled. For each center, the required information was extracted from local supportive care guidelines, and the list was sent to a pediatric oncologist of that center to verify its correspondence with local daily practice. Subsequently, it was determined whether clinical practice was concordant (same in ≥ 5 of 6 centers), partly concordant (highly overlapping in ≥ 5 of 6 centers), or discordant (same in < 5 of 6 centers). Local practices were compared with strong recommendations from high-quality, evidence-based guidelines. The questionnaire comprised 67 questions regarding supportive care practice. Concordance was observed for 11 of 67 practice items (16%), partial concordance was observed for 6 of 67 practice items (9%), and discordance was observed for 50 of 67 practice items (75%). Adherence to strong recommendations of 4 high-quality, evidence-based guidelines varied but was generally low. Large variations exist in pediatric oncology supportive care practice, and this could negatively influence care. Adherence to existing evidence-based guidelines and the development and implementation of new clinical practice guidelines have the potential of standardizing supportive care practice and thereby improving outcomes for children with cancer.

Quantitative Assessment of Free Flap Viability with CEUS Using an Integrated Perfusion Software.

New treatment strategies in oncology and trauma surgery lead to an increasing demand for soft tissue reconstruction with free tissue transfer. In previous studies, CEUS was proven to detect early flap failure. The aim of this study was to detect and quantify vascular disturbances after free flap transplantation using a fast integrated perfusion software tool. From 2011 to 2013, 33 patients were examined by one experienced radiologist using CEUS after a bolus injection of 1-2.4 ml of SonoVue(®). Flap perfusion was analysed qualitatively regarding contrast defects or delayed wash-in. Additionally, an integrated semi-quantitative analysis using time-intensity curve analysis (TIC) was performed. TIC analysis of the transplant was conducted on a centimetre-by-centimetre basis up to a penetration depth of 4 cm. The 2 perfusion parameters "Time to PEAK" and "Area under the Curve" were compared in patients without complications vs. patients with minor complications or complete flap loss to figure out significant differences. TtoPk is given in seconds (s) and Area is given in relative units (rU) Results: A regular postoperative process was observed in 26 (79%) patients. In contrast, 5 (15%) patients with partial superficial flap necrosis, 1 patient (3%) with complete flap loss and 1 patient (3%) with haematoma were observed. TtoPk revealed no significant differences, whereas Area revealed significantly lower perfusion values in the corresponding areas in patients with complications. The critical threshold for sufficient flap perfusion was set below 150 rU. In conclusion, CEUS is a mobile and cost-effective opportunity to quantify tissue perfusion and can even be used almost without any restrictions in multi-morbid patients with renal and hepatic failure.

Imaging tumour response - challenges

RECIST criteria use changes in tumour diameters to quantitatively obtain response assessments for traditional chemotherapeutic cancer treatments: Positive responses are identified by reductions in tumour size while tumour growth signifies non-response. Traditional chemotherapies work primarily by damaging cells that are undergoing rapid growth and division. Immunotherapies work by stimulating the immune system to reject and destroy tumour cells. Targeted cancer therapies block the growth of cancer cells by interfering with specific molecules needed for tumour growth and carcinogenesis. These oncological treatments as well as stereotactic radiation therapy and local treatments, such as image-guided ablations and transarterial chemo embolization (TACE) can be used alone or in combination. Local treatment, radiation therapy, immunotherapy and targeted therapy can each result in an increased tumour diameter in spite of treatment response at the cellular level and increased survival times. As a result, tumour diameter can no longer stand alone when assessing oncological treatment strategies Tumour heterogeneity and contrast enhancement often change during treatment, and tumour enhancement combined with tumour size has been shown to be successful in assessing treatment response in gastrointestinal stromal tumours (CHOI criteria). Modified CHOI criteria could potentially be used for monitoring the effect of oncological treatment strategies in metastatic renal cell cancer and hepatocellular carcinoma. Dynamic contrast-enhanced imaging (DCE-US, DCE-MRI and DCE-CT) uses changes in tumour enhancement following the intravenous injection of a contrast media to create a time-versus-signal curve. From such curves, reliable quantitative estimates of blood flow, blood volume and permeability can be obtained. Diffusion-weighted MRI and PET can also be used to obtain quantitative measures of physiological processes. A major advantage of DWI-MRI and PET is the possibility of whole body coverage, while DCE imaging is limited to a single tumour or a comparatively small region. Although quantitative assessments of oncological treatment response using physiological parameters have been shown to be superior to size-based response in several studies, the methods mentioned are not yet standardized, and randomized multicentre studies have not yet been performed. When planning such studies, it is important to note that clinical endpoints such as progression free survival and overall survival are superior to morphological imaging results. In the routine assessment of oncological treatment responses, it is becoming increasingly important for the radiologists to know exactly what kind(s) of treatment that the patient has received. Simply reporting changes in tumour size using RECIST is no longer sufficient considering the large percentage of patients who receive advanced and often combined treatment regimens.

Comparative Pharmacokinetics and Allometric Scaling of Carboplatin in Different Avian Species.

The use of chemotherapeutics as a possible treatment strategy in avian oncology is steadily increasing over the last years. Despite this, literature reports regarding dosing strategies and pharmacokinetic behaviour of chemotherapeutics in avian species are lacking. The aim of the present study was to investigate the pharmacokinetics of carboplatin in a representative species of the order of Galliformes, Anseriformes, Columbiformes and Psittaciformes. Eight chickens, ducks and pigeons and twenty-eight parakeets were administered carboplatin intravenously (5 mg/kg body weight). A specific and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for quantification of the free carboplatin in plasma of the four birds species (limit of quantification: 20 ng/mL for chicken and duck, 50 ng/mL for pigeon and 100 ng/mL for parakeets). Non-compartmental pharmacokinetic analysis and allometric scaling demonstrated a significant correlation (R² = 0.9769) between body weight (BW) and elimination half-life (T1/2el). T1/2el ranged from 0.41 h in parakeets (BW: 61 ± 8 g) to 1.16 h chickens (BW: 1909 ± 619 g). T1/2el is a good parameter for dose optimization of carboplatin in other avian species, since also the previously reported T1/2el in cockatoos (average BW: 769 ± 68 g) of 1.00 h corresponds to the results obtained in the present study.

Surgical resection of metastases to the adrenal gland: a single center experience.

Only limited data exist on the treatment and outcome of adrenal metastases that derive from different primary tumor entities. Due to the lack of evidence, it is difficult to determine the indication for surgical resection. We assessed the outcome of 45 patients (28 men, 17 women) with adrenal metastases who underwent surgery (1990-2014). The median age at the time of adrenal surgery was 62 years (range 44-77 years). We were able to evaluate follow-up data of 41 patients. Primary tumor types were liver n = 12 (hepatocellular carcinoma n = 9, cholangiocellular carcinoma n = 2, sarcoma n = 1), upper GI tract n = 5 (esophagus n = 2, stomach n = 3), lung n = 9, kidney n = 6, neuroendocrine tumors n = 3, colon n = 2, ovarial n = 2, melanoma n = 2, others n = 4. The overall median survival time was 14 months (95 % CI 8.375-19.625). The survival rates at 1, 2, 5, and 10 years were 60, 31, 21, and 11 %, respectively. There were statistically significant differences in the survival time according to the resection status (R0 vs. R1/R2) (p < 0.001) and the type of the primary tumor (p = 0.009), while the metachronous or synchronous occurrence of adrenal metastases did not affect the prognosis. Resection of adrenal metastases can improve the survival if patients are carefully selected, the tumor is completely resected, and the intervention is integrated into a multidisciplinary oncologic treatment strategy.

Irradiation treatment of metastatic tumors and lymphomas

AbstractIntraocular metastases are usually uveal, secondary to breast or lung carcinoma. Lymphoma is most frequently vitreoretinal, in a context of primary central nervous system lymphoma, while a uveal location points towards systemic lymphoma. Management is influenced by a palliative context and bilateral ocular involvement. Close collaboration with the oncologist is required as to the histopathology of the primary tumor, its global extent, oncologic treatment strategy and life expectancy. Stereotactic irradiation is often the principal ocular treatment. A circumscribed treatment of individual lesions carries the risk of local recurrences. The hemato‐ocular barrier often prevents chemotherapy from being effective within the uvea. Radiotherapy usually allows a quick reattachment of the retina and preservation of vision. Evolution towards a painful globe and enucleation should be avoided. With the increasing life expectancy of oncologic patients, treatment of ischemic retina with anti‐VEGFs and PRP becomes more indicated. Conclusion: Irradiation of intraocular metastases and lymphomas is the most important tool in preserving vision and the eye(s). Its indication should be made within a global oncologic treatment strategy.

Oncologic efficacy of angiolytic KTP laser treatment of early glottic cancer.

Angiolytic laser removal of early glottic cancer with ultra-narrow margins was reported in a pilot study 5 years ago as an innovative surgical treatment strategy to better preserve vocal function. Subsequently, in a cohort of > 90 patients, enhanced voice outcomes were achieved and there was diminished need for post-treatment phonosurgical reconstruction. However, the initial pilot study examining oncologic efficacy had a limited number of patients and most did not have 3-year follow-up. Consequently, further analysis of the oncologic efficacy is valuable. Retrospective review. One hundred seventeen patients (T1a-71, T1b-11, T2a-10, T2b-25) underwent potassium-titanyl-phosphate (KTP) laser treatment of early glottic cancer with a minimum 3-year follow-up (average = 53 months). The "b" designation delineated bilateral disease. Disease control for T1 and T2 lesions was 96% (79/82) and 80% (28/35), respectively. All 10 recurrences were treated with radiotherapy. Fifty percent (5/10) were controlled with radiotherapy, and the other 5 died of disease. Larynx preservation and survival were achieved in 99% (81/82) with T1 disease and 89% (31/35) with T2 disease. This investigation provides further evidence that angiolytic KTP laser removal of early glottic cancer with ultra-narrow margins is an effective oncologic treatment strategy. Radiotherapy was preserved for future use in more than 90% of patients. Since a majority of patients are referred by an otolaryngologist to undergo treatment of early glottic cancer with radiotherapy, this investigation provides compelling information to reappraise this paradigm.

Barriers to the Access and Use of Rituximab in Patients with Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia: A Physician Survey.

Biologics such as rituximab are an important component of oncology treatment strategies, although access to such therapies is challenging in countries with limited resources. This study examined access to rituximab and identified potential barriers to its use in the United States, Mexico, Turkey, Russia, and Brazil. The study also examined whether availability of a biosimilar to rituximab would improve access to, and use of, rituximab. Overall, 450 hematologists and oncologists completed a survey examining their use of rituximab in patients with non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Less than 40% of physicians considered rituximab as easy to access from a cost perspective. Furthermore, many physicians chose not to treat, were unable to treat, or had to modify treatment with rituximab despite guidelines recommending its use in NHL and CLL patients. Insurance coverage, reimbursement, and cost to patient were commonly reported as barriers to the use of rituximab. Across all markets, over half of physicians reported that they would increase use of rituximab if a biosimilar was available. We conclude that rituximab use would increase across all therapy types and markets if a biosimilar was available, although a biosimilar would have the greatest impact in Brazil, Mexico, and Russia.

ALPPS for Patients with Colorectal Liver Metastases: Effective Liver Hypertrophy, but Early Tumor Recurrence

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a promising method to increase resectability rates of liver tumors. Little has been published about oncological results so far. This report describes clinical evidence regarding a possible effect of ALPPS on tumor recurrence. Ten ALPPS procedures were performed for otherwise non-resectable colorectal liver metastases. Seven of these ten patients had a follow-up of at least 3 months and were analyzed for tumor recurrence. Six of these seven patients had tumor recurrence to the liver. Three of seven patients presented with lung metastases, occurring earlier than liver metastases in two of three cases. One patient with a follow-up of 3 months had no visible recurrent disease, but increasing carcinoembryonic antigen levels. The patient group operable only through ALPPS is at high risk for recurrence and early tumor progression. Still, this new method is the only chance for an oncological treatment strategy including a surgical approach and possibly better outcome.

Factors associated with early recurrence and death after esophagectomy for cancer

Accurate selection of patients for radical treatment of esophageal cancer is essential to avoid early recurrence and death (ERD) after surgery. We sought to evaluate a large series of consecutive resections to assess factors that may be associated with this poor outcome. This was a cohort study including 680 patients operated for esophageal cancer between 2000 and 2010. The poor outcome group comprised 100 patients with tumor recurrence and death within 1 year of surgery. The comparison group comprised 267 long-term survivors, defined as those surviving more than 3 years from surgery. Pathological characteristics associated with poor outcome were analyzed using logistic regression to determine odds ratios (OR) and 95% confidence intervals (CI). On the adjusted model T stage and N stage predicted poor survival, with the greatest risk being patients with locally advanced tumors and three or more involved lymph nodes (OR 10.6, 95% CI 2.8-40.0). Poor differentiation (OR 2.8, 95% CI 1.4-5.5), chemotherapy response (OR 3.6, 95% CI 1.2-10.6), and involved resection margins (OR 2.7, 95% CI 1.2-6.0) were all significant independent prognostic markers in the multivariable model. There was a trend toward worse survival with lymphovascular invasion (OR 2.0, 95% CI 0.9-4.2) and low albumin (OR 1.9, 95% CI 0.8-4.4) but not of statistical significance in the adjusted model. Esophageal cancer patients with poorly differentiated tumors and three or more involved lymph nodes have a particularly high risk of ERD after surgery. Accurate risk stratification of patients may identify a group who would be better served by alternative oncological treatment strategies.

Abstract 3350: Plucked hair as a biomarker platform for monitoring transcriptional consequences of clinical exposure to antagonism of the HDM2/P53 interaction in tumors.

Abstract The ability to assess and monitor target engagement is crucial for informing early drug development decisions. High vascularisation of the hair follicle, frequent epithelial origin of tumors, and high degree of congruence of expression in hair of pathways dysregulated in cancers, makes the cellular bulb on plucked human scalp hair an excellent surrogate tissue for non-invasive monitoring of PD effects in clinical trials. Disruption of the p53-HDM2 interaction with small molecules has demonstrated single agent anti-tumor activity in preclinical models and represents an attractive treatment strategy in oncology. Development of a peripheral tissue based gene expression signature of inhibition of the p53-HDM2 interaction could facilitate the early development of these compounds. To develop a peripheral PD biomarker of antagonism of this interaction, we used two selective p53-HDM2 antagonists, Nutlin-3 and Sanofi's SAR405838 and applied our plucked hair biomarker platform to develop a gene expression signature indicative of compound exposure. SAR405838 displays potent activity in vitro and in vivo against p53 WT cell lines / xenograft models, but not in the p53 mutant context. Three hairs from each of four healthy donors were exposed to either SAR405838 or Nutlin-3 over a range of compound concentrations for 6hr or 24hr in our proprietary ex vivo cultures. We extracted RNA from the cellular bulb of individual hairs and assessed the transcriptome by microarray analysis. Biological enrichment analysis of genes differentially expressed revealed strong correlation to activated P53 signaling pathways. Further analysis revealed a core set of congruent genes as candidate PD biomarkers of p53-HDM2 antagonism, one of which was MIC-1, a secreted plasma protein that demonstrates a strong PK/PD relationship in patients treated with p53-MDM2 antagonists in Phase 1 trials. In ex vivo plucked hair, we have demonstrated biologically relevant differential expression of a panel of transcriptional markers exhibiting common response to Nutlin-3 and SAR405838. These reflect compound mechanism of action, and can provide further evidence of target engagement in addition to plasma MIC-1 levels. While the temporal and kinetic relationship between gene expression changes, toxicity, and clinical efficacy remains to be determined, the genes identified in this study may be used to provide further MOA information in clinical settings to monitor PD responses in plucked scalp hair obtained from patients exposed to SAR405838. Citation Format: Gino Miele, Elliot Harrison, Tim Mefo, Jo Read, Lydia Meyer Turkson, Alan Murdoch, Michael Teufel, Laurent Debussche, Donald Bergstrom, James Watters. Plucked hair as a biomarker platform for monitoring transcriptional consequences of clinical exposure to antagonism of the HDM2/P53 interaction in tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3350. doi:10.1158/1538-7445.AM2013-3350

Image-guided percutaneous ablation therapies for local recurrences of thyroid tumors

The incidence of thyroid carcinoma has increased steadily over the last few decades. Most differentiated thyroid carcinomas (DTC) are cured thanks to the initial treatment with surgery and radioiodine therapy. Nevertheless, neck lymph node metastases are found in a few of these patients during their long-term clinical and ultrasound follow-up. In some of these cases radioiodine treatment may not be effective in eradicating nodal metastases due to scant 131-I uptake. Additionally, a few of these patients undergo repeated neck explorations and/or resections. Based on these considerations and on the frequently indolent course of DTC neck metastases, a non-surgical therapeutic approach should be considered to control small local foci of DTC. There is increasing interest in mini-invasive image-guided procedures that can be performed under local anesthesia which do not affect the performance status of the patient. Image-guided minimally invasive ablative therapies delivered by using needle-like applicators include both thermal and non-thermal source techniques. Over the past 25 years, these therapies have gained widespread attention and, in many cases, broad clinical acceptance as methods for treating focal malignancies. In an attempt to overcome the limitations of treating certain unresectable tumor types not amenable to a further surgical treatment, a few investigators have reported successfully combining percutaneous therapies with other oncologic treatment strategies (combined treatments). In this review, we reported mini-invasive techniques more commonly employed in selected cases to ameliorate local compressive symptoms, control hormonal production, and reduce the volume of neoplastic tissue prior to traditional palliative treatment.

100% Human Monoclonal Antibodies in Oncology: Hype or Breakthrough?

Targeted therapies have dramatically modified treatment strategies in oncology since the early 2000's, especially for treating digestive cancers. These new biotherapies such as anti-VEGF (bevacizumab) or anti-EGFR (cetuximab) monoclonal antibodies have given oncologists new opportunities to use innovative treatment schedules or combinations with cytotoxics. Consequently, significant improvements in response rates, with trends to longer progression-free survival and/or overall survival have been achieved in patients with metastatic colorectal cancer (mCRC). Panitumumab is a novel, 100% human, anti-EGFR1 (HER1) antibody that has been approved in late 2007 for use as monotherapy in mCRC patients resistant to standard chemotherapy, provided that their tumor express EGFR and display wild-type K-Ras status. Panitumumab has been recently further approved in combination with chemotherapy in mCRC patients. However, owing to the fact that its mechanism of action for targeting EGFR is similar to that of chimeric cetuximab, picturing the specificities in pharmacological and pharmacokinetic properties of this 100% human antibody could help the oncologists to better define their strategies at the bedside.

Tumoral predominance and oncologic treatment possibilities of older patients in Argentina.

e19682 Background: Age is one of the principal factors to determine the most adequate oncological treatment strategy. The increased life expectancy had an impact in the number of aged patients with cancer, thus the way these patients are treated should be revised. The aged patients group, over 65 years old, are the 16% of the total populations, but the portion of them suffering cancer are around the 60%. Objective: to describe the profile of our aged patients (over 65 years old) stratified according the clinical and therapeutic possibilities. Methods: Retrospective, descriptive and comparative study in which they have evaluated patients admitted at the Centro Oncológico Buenos Aires, during the period from January 2004 until December 2007. A total of 1457 patients were evaluated (range from 16 to 94 years old), all of them with confirmed diagnostic of cancer (histological exam) 54% (787 patients) were under 65 years of age and 46% remaining (670 patients) were between 65 to 94 years of age. Results: Tumor vs age (years mean ±standard deviation-sdt-) urologic tumors 70±6, sarcoma 69±8, lung 69±5, prostate 69±4, unknown primary 68±4, skin 70±6, hematologic 70±5, mesotelioma 66±1, melanoma 72±9, breast 69±5, gynecologic 71±8, gastroenterology 71±7, head and neck 72±8, colorectal 70±6; treatment vs age (years mean±sdt) radiotherapy 70±9, radiotherapy +hormothetrapy, 69±4, radiotherapy 70±7, chemotherapy + radiotherapy + hormotherapy,69±6, chemotherapy + radiotherapy, 69±5, chemotherapy + hormotherapy, 72±9, chemotherapy 70±6, and hormotherapy 71±3. There were not statistical differences among groups. Conclusions: Our study confirms that: the impact of cancer in patients over 65 years in our environment is similar to that observed in other so-called developed countries (USA and Europe) despite of cultural, nutritional and hygienic differences.We can make cancer treatments (surgery, radiotherapy, chemotherapy, hormotherapy and others) in this patient group. The age should not be the only parameter to decide the treatment. The comorbidities should be taken into account when deciding on a therapeutic behavior. No significant financial relationships to disclose.

Abstract 709: The fully human IGF-1 receptor antibody, CP-751,871, targets putative colon cancer stem cell populations

Abstract The identification of cancer stem cells (CSCs) has the potential to provide answers to questions of tumor pathogenesis, metastasis, and therapeutic resistance. We have previously shown that insulin-like growth factor 1 (IGF-1) enriches putative colon CSC populations, an important finding with the potential to explain the association of colon cancer risk and chemoresistance with the levels of circulating IGF-1 and obesity. Here, we have employed three established methods (side population (SP) analysis, aldehyde dehydrogenase activity (ALDH+), and CD133 expression) to analyze a panel of 8 human colon cancer cell lines for putative cancer stem cell properties. We have found enrichment of SP and/or ALDH+ populations across the panel of 8 colon cancer cell lines, as well as many lines originating from other tissues. The enrichment of SP cells by IGF-1 is independent of altered ABC transporter activity as measured by mitoxantrone efflux. Enrichment of CSCs by IGF-1 does not appear to depend on the activity of MAP kinases (based on inhibition with PD098059 and U0126); therefore, we are currently exploring dependence on alternative IGF signaling pathways downstream of Akt, including NF-κB and mTOR. While we continue our efforts to unravel the mechanism by which IGF-1 enriches CSCs we are also interested in the more immediate clinical implications of our findings. CP-751,871 is a fully human antibody with specificity to the IGF-1 receptor and is currently being tested in clinical trials for a variety of solid malignancies. We have found that CP-751,871 reduces both SP and ALDH+ CSC populations in multiple colon cancer cell lines in vitro, and has promising activity against these populations in pilot experiments in vivo. We are currently repeating these studies to yield conclusions supported by statistics. Interestingly, CP-751,871 blocks IGF-1 enrichment of the side population in DLD1 cells, but not in SW480 cells suggesting a potential role of alternative receptors, such as the insulin receptor in some cell lines, a possibility we are currently analyzing. These studies have the potential to affect clinical oncology treatment strategies as the role of CSCs in tumor growth is delineated. Our results suggest that CP-751,871 has preferential activity against putative CSC populations, and therefore, may benefit current standard chemotherapeutic regimens that target cycling cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 709.

Efficacy of rituximab in gastric diffuse large B cell lymphoma patients

To evaluate retrospectively the efficacy of rituximab plus chemotherapy in gastric diffuse large B cell lymphoma (DLBCL). Sixty patients (median age: 58 years) with histologically confirmed gastric DLBCL treated at four Italian institutions between 2000 and 2007, were included in this analysis. Patients were selected by stage (I-IV, Lugano staging system), European Cooperative Oncology Group performance status (0-2) and treatment strategies. Treatment strategies were chemotherapy alone (group A, n = 30) [scheduled as cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and CHOP-like], and chemotherapy combined with rituximab (group B, n = 30). The primary end point of the study was complete response (CR) rate; the secondary end points were disease-free survival (DFS) at 5 years and overall survival (OS). Median follow-up was 62 mo (range: 31-102 mo). We observed a significant difference between the two groups (A vs B) in terms of CR [76.6% (23/30) vs 100%, P = 0.04) and DFS at 5 years [73.3% (22/30) vs 100%, P = 0.03). To date, 19 group A (63.3%) patients are alive and 11 have died, while all group B patients are alive. No significant differences in toxicity were observed between the two groups. Rituximab in combination with chemotherapy improves CR rate, DFS and OS. Further prospective trials are needed to confirm our results.

Angiogenesis/tumor hypoxia: new treatment options?

Angiogenesis/tumor hypoxia: new treatment options?

On the Eve of Personalized Medicine in Oncology

The future of cancer care and treatment lies in the concept of “personalized medicine,” a model that focuses on the individual, not just the disease. Personalized medicine in cancer care will need to use molecular signatures to match the right patients to the right drugs, first in clinical