Conventional Chemotherapy Agents Research Articles

Salvage regimens using conventional chemotherapy agents for relapsed/refractory adult AML patients: a systematic literature review.

Prognosis in relapsed and refractory acute myeloid leukemia (R/R AML) patients is dismal, with no satisfactory and standard salvage chemotherapy regimen. We performed a systematic review in order to analyze the clinical outcomes reported with conventional chemotherapy schemes in adult patients with R/R AML. To have a better understanding of the R/R ground, we included studies in R/R AML adult population at any disease stage (i.e., primary refractory as well as first relapse or beyond). Study selection included a total number of 157 out of 850 records, with a wide variety of schedules. Furthermore, only 24 studies were randomized clinical trials (RCTs), being the majority of the studies retrospective analyses in small cohorts. This review reveals that several intensive regimens (cytarabine + mitoxantrone + etoposide or gemtuzumab, and cytarabine + purine analogue ± antracycline) achieve relatively high complete remission (CR) rates (44 to 59.4%). However, most of these schemes did not obtain substantial CR duration (4.9 to 9.8months) or overall survival (6.2 to 8.7months). In unfit/vulnerable patients non-intensive approaches are recommended to control disease progression and minimize treatment-related mortality. A better knowledge of the prognostic factors, more effective and less toxic combinations using conventional and new therapies, as well as improvements in allo-HSCT procedure and timing, could play a role to improve the clinical outcomes in the future. Clinical trials should be the first treatment option in R/R AML, both in fit and unfit patients.

25IN - The relationship between DNA damage and immune checkpoint activation in cancer

Background: In cancer the presence of T cell immune infiltration has been recognised as a prognostic factor, however the mechanisms underpinning this response are not clearly defined. Our group and others have identified a relationship between type I Interferon immune signalling and loss of DNA repair, particularly the Fanconi Anemia pathway, in several different types of cancer. We therefore investigated the mechanism activating this immune response in the context of abnormal DNA repair. Methods: Preclinical isogenic cell line systems and human tumours were used to identify the relationship between loss of function of DNA repair genes and activation of immune signalling. A panel of Chemotherapeutic agents were studied for their effect on immune activation. Results: IHC analysis demonstrated that both intra-tumoral and stromal CD8+ and CD4+ T cell infiltration were associated with DNA repair deficient breast tumors. The CXCL10 and CCL5 cytokines as well as the immune checkpoint target PD-L1 were shown to be significantly up-regulated in DNA repair deficient tumours and in tissue culture models when compared to DNA proficent tumours. Furthermore, conditioned media from DNA repair deficient cell lines stimulated inward migration of peripheral blood mononuclear cells, when compared to media from proficient cells, indicating the presence of active cytokines. We identified constitutive activation of the innate immune pathway STING/TBK1/IRF3 specifically in DNA repair deficient tumour cells when compared to proficient cells and found that binding of the DNA sensor cGAS to cytosolic DNA fragments was required for this immune response. In addition, we identified several chemotherapeutic agents that were able to activate the immune response in DNA repair proficient cell lines through DNA damage, the development of cytoplasmic DNA fragments and the consequent activation of the STING/TBK1/IRF3 immune pathway. Conclusions: We have identified that the STING/TBK1/IRF3 immune pathway is constitutively activated by cytoplasmic DNA in DNA repair deficient cancers and may explain lymphocytic infiltration and the response to immune checkpoint based therapy. Some conventional chemotherapy agents such as doxorubicin are able to active this pathway in DNA repair proficient cancers and may represent a logical combination with immune checkpoint targeted drugs in clinical trials. Legal entity responsible for the study: Queen's University of Belfast Funding: McClay Foundation Disclosure: R. Kennedy: I receive payment as the Global VP and Medical Director for Almac Diagnostics.

Ruxolitinib synergistically enhances the anti-tumor activity of paclitaxel in human ovarian cancer.

Treatment for ovarian cancer remains challenging despite a high initial response rate to first line platinum-taxane treatment. Most patients eventually experience recurrence and require further treatment. Persistent activation of STAT3 is associated with cancer growth and progression and is also involved in cell resistance to platinum and taxane treatment. Targeting JAK/STAT3, therefore, could be a potential novel therapeutic approach for treating advanced and chemoresistant ovarian cancer. We investigated the therapeutic potential of ruxolitinib, a JAK1/JAK2 inhibitor that has been FDA-approved for the treatment of myelofibrosis, to treat ovarian cancer either alone or in combination with conventional chemotherapy agents. We show that ruxolitinib inhibits STAT3 activation and ovarian tumor growth both in ovarian cancer cells and in an ovarian cancer mouse model. In addition, ruxolitinib significantly increases the anti-tumor activity of chemotherapy agents, including paclitaxel, cisplatin, carboplatin, doxorubicin and topotecan in ovarian cancer cells. Evaluation of the combination index (CI) shows that ruxolitinib synergistically interacts with paclitaxel in all three human ovarian cancer cells. Finally, our results demonstrate that combination of ruxolitinib and paclitaxel leads to a greater reduction of tumor growth compared to single treatment of either agent in a tumor mouse model that represents late stage ovarian cancer with peritoneal metastasis and ascites formation. Taken together, our findings provide a foundation for clinical trials with ruxolitinib, either as a single agent or in combination with paclitaxel, for the treatment of recurrent and advanced ovarian cancer.

Inhibition of autophagy enhances synergistic effects of Salidroside and anti-tumor agents against colorectal cancer

BackgroundVarious plant extracts have been suggested to be used as auxiliary agents in chemotherapy considering their anti-proliferative effect on cancer cells. However, recent reports reveal that plant extracts may function as inducers of autophagy of cancer cells. In general, autophagy confers survival advantage for cells responding to stress conditions, thus representing an important mechanism for chemo-resistance. This study was aimed to investigate the effectiveness of combined use of Salidroside (Sal, a phenylpropanoid glycosides from Rhodiola rosea L) with anti-tumor agents against colorectal cancer (CRC) cells, and moreover to evaluate the potential role of autophagy in the combined therapy.MethodsCRC cells, HCT-116, were incubated with Sal alone or in combination with conventional chemotherapy agents including oxaliplatin (OXA), 5-fluorouracil (5-FU) and Doxorubicin (ADM). Cell proliferative characteristics were evaluated by cell viability and apoptosis rate. The protein expression was assessed by Immunofluorescent and Western blot assays.ResultsSal, alone or in combination with anti-tumor agents, increased expression of autophagic biomarkers, including LC3B and Becline-1, suggesting an autophagy induction. Except for the up-regulation of p-AMPK, p-mTOR, p-NF-κB (p65), TGF-β, p-JAK2 and p-STAT3 were down-regulated by Sal. Because autophagy is positively correlated with the activation of AMPK/mTOR, NF-κB, TGFβ1 and JAK2/STAT3 cascades, the autophagy induced by Sal may associate with AMPK activation. Indeed, blockage of AMPK signaling via Compound C or AMPK knockdown inhibited the autophagy. The blockage of AMPK signaling or a direct inhibition of autophagy via 3-MA increased effectiveness of combined use of Sal with anti-tumor agents against CRC.ConclusionsInhibition of autophagy enhances synergistic effects of Sal and anti-tumor agents against colorectal cancer. This study provides experimental evidence and theoretical reference for improvement of a novel chemotherapy treatment protocol.

PI3K/AKT/mTOR Pathway in Ovarian Cancer Treatment: Are We on the Right Track?

The high recurrence rate and the low overall survival in ovarian cancer suggest that a more specific therapeutic approach in addition to conventional treatment is required. Translational and clinical research is investigating new molecular targets in order to find an alternative way to affect tumor growth and to minimize the overlap of toxicity of antiblastic agents. Given its implication in many cellular activities including regulation of cell growth, motility, survival, proliferation, protein synthesis, autophagy, transcription, as well as angiogenesis, PI3K/AKT/mTOR is one of the most investigated intracellular signaling pathways. A dis-regulation of this pathway has been shown in several tumors, including ovarian cancer. In this setting, mTor proteins represent a potential target for inhibitors, which could ultimately play a pivotal role in counteracting cellular proliferation. Recently, mTor inhibitors have been approved in the treatment of pancreatic neuroendocrine tumors, mantle cell lymphoma and renal cancer. Clinical trials have assessed the safety of these drugs in ovarian cancer patients. Ongoing phase I and II studies are evaluating the oncologic outcome of mTor inhibitor treatment and its effect in combination with conventional chemotherapy and target agents.

Abstract 2775: CPS1 as a therapeutic target and prognostic indicator in LKB1-inactivated lung adenocarcinoma

Abstract Liver Kinase B1 (LKB1), encoded by STK11, is a tumor suppressor and somatically mutated in approximately 20% of lung adenocarcinoma. Aside from the effects of LKB1 inactivation on tumor initiation, LKB1-mutant cancers are biologically distinct from cancer with functional LKB1, and the loss of LKB1 uniquely confers invasive and metastatic properties in genetically engineered mouse models of cancer. While various pathways, including energy metabolism, cell polarity, and cell growth, are regulated by LKB1 and can play a pleiotropic role in cancer initiation and progression, no therapies are currently available for clinical use that specifically target LKB1 inactivation. Therefore, elucidation of the functional mechanisms associated with LKB1 inactivation has translational relevance. We analyzed proteomic profiles of 45 lung adenocarcinoma cell lines with and without LKB1 inactivation to identify molecular features associated with LKB1 inactivation. Carbamoyl phosphate synthase 1 (CPS1) was identified as a markedly overexpressed protein in LKB1-inactivated lung adenocarcinoma cell lines. CPS1 is the first rate-limiting mitochondrial enzyme in the urea cycle, and plays an intricate role in arginine and pyrimidine metabolism. CPS1 knockdown reduced cell growth, decreased levels of metabolites associated with nucleic acid biosynthesis pathway, and contributed an additive effect when combined with conventional chemotherapy agents including gemcitabine, pemetrexed, or CHK1 inhibitor AZD7762. Tissue microarray analysis using 305 lung adenocarcinoma tumors revealed that CPS1 was expressed in 65.7% of LKB1-negative and only 5.0% of LKB1-positive lung adenocarcinomas. In addition, CPS1 expression was significantly and independently associated with poor overall survival of lung adenocarcinoma patients (P < 0.0001, HR = 3.03, 95% CI 1.74-5.25). Concordant with the results of tissue microarray, analysis of the Cancer Genome Atlas (TCGA) dataset consisting 403 lung adenocarcinomas revealed that high CPS1 mRNA expression was significantly associated with worse overall survival and is an independent prognostic indicator of lung adenocarcinoma (P = 0.005, HR = 2.31, 95% CI 1.28-4.16). Our findings suggest functional relevance of CPS1 and its association with worse outcome in LKB1-inactivated lung adenocarcinoma. Therefore, CPS1 is a promising therapeutic target in combination with other chemotherapy agents, as well as a prognostic biomarker, enabling us to personalize the treatment of LKB1-inactivated lung adenocarcinoma. Citation Format: Muge Celiktas, Ichidai Tanaka, Satyendra Chandra Tripathi, Johannes F. Fahrmann, Clemente Aguilar-Bonavides, Pamela Villalobos, Oliver Delgado, Dilsher Dhillon, Jennifer B. Dennison, Edwin J. Ostrin, Hong Wang, Carmen Behrens, Kim-Anh Do, Adi F. Gazdar, Samir M. Hanash, Ayumu Taguchi. CPS1 as a therapeutic target and prognostic indicator in LKB1-inactivated lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2775. doi:10.1158/1538-7445.AM2017-2775

Core–Shell Metal-Organic Frameworks as Fe2+ Suppliers for Fe2+-Mediated Cancer Therapy under Multimodality Imaging

Integrated theranostic agents can provide comprehensive and efficient tools for simultaneous cancer diagnosis and therapy; however, limitations on efficiency and safety offer great room for improvement. Artesunate (AS), as an iron-dependent drug, has been investigated in cancer therapy, depending on free-radical generation for its action, which may reduce side effects commonly associated with conventional chemotherapy agents with low selectivity to target tumors. However, rapid clearance of its free form and limited availability of Fe ion in tumor sites become the main bottlenecks in cancer therapy. Herein, core–shell Mn3[Co(CN)6]2@MIL-100(Fe) metal-organic frameworks (CS-MOFs) nanocube was designed using a layer-by-layer method, which holds great potential for synchronous co-delivery of AS and ferric ions for cancer therapy. Moreover, the heterogeneous hybrid CS-MOFs show single- and two-photon fluorescence, together with T2 and enhanced T1 magnetic resonance imaging ability. pH-responsive degradation of...

Targeted therapy for soft tissue sarcomas in adolescents and young adults.

Soft tissue sarcomas (STSs) are a heterogeneous group of tumors originating from the mesenchyme. Even though they affect individuals in all age groups, the prevalence of subtypes of STSs changes significantly from childhood through adolescence into adulthood. The mainstay of therapy is surgery, with or without the addition of chemotherapy and/or radiation therapy. These treatment modalities are associated, in many cases, with significant morbidity and, given the heterogeneity of tumor histologies encompassed by the term “STS”, have not uniformly improved outcomes. Moreover, some subgroups of STSs appear to be more, and others less, responsive to conventional chemotherapy agents. Over the last two decades, our understanding of the biology of STSs is slowly increasing, allowing for the development of more targeted therapies. We review the new treatment modalities that have been tested on patients with STSs, with a special focus on adolescents and young adults, a group of patients that is often underrepresented in clinical trials and has not received the dedicated attention it deserves, given the significant differences in biology and treatment response in comparison to children and adults.

A review on adverse event profiles of epidermal growth factor receptor-tyrosine kinase inhibitors in nonsmall cell lung cancer patients.

The epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of EGFR-mutant nonsmall cell lung cancer (NSCLC). These EGFR TKIs demonstrate a different adverse event (AE) profile as compared to conventional chemotherapy agents. They are more commonly associated with cutaneous AEs and diarrhea while hematological AEs occurred commonly with chemotherapy agents. These AEs are the extension of pharmacological effect and occur as a result of blockade of EGFR-regulated pathways in the skin and gastrointestinal tract. This review article sheds light on the safety profile of first-, second-, and third-generation EGFR TKIs based on data obtained from several clinical trials conducted in NSCLC patients and highlights trials comparing these agents with the conventional chemotherapy agents. The strategies to manage EGFR TKI-related AEs are also reviewed.

Everolimus Is Active in Pretreated Hodgkin Lymphoma after Failure of Brentuximab Vedotin: Single Institute Experience

Introduction: Patients with Hodgkin lymphoma (HL) relapsing after ASCT and those not eligible for myeloablative therapy can be salvaged with conventional chemotherapy or new novel agents such the immunotoxin brentuximab vedotin and the recently FDA approved anti-PD-1 inhibitor nivolumab. Other options include the mTOR inhibitor everolimus (1) for which, the data in literature is scarce. Moreover, there is no data on the efficacy of everolimus after failure of brentuximab vedotin.Patients and methods: In this study, we retrospectively analyzed the outcome of patients with relapsed/ refractory HL treated with single agent everolimus at our center between July 2015 and July 2016. All patients were started on everolimus 10 mg daily. Response to treatment was assessed every 2 months. Primary endpoint was the response rate of everolimus as single agent in patients with relapsed/refractory HL.Results: We identified 5 patients with heavily pretreated HL who received single agent everolimus. Mean age was 24.4 years (range, 20-30). Mean lines of previous treatment was 6.4 (range, 5-8). All patients failed brentuximab vedotin. Two patients failed previous autologous stem cell transplantation. Prior treatments included ABVD, radiation, ICE, ESHAP, miniBEAM, GVD, brentuximab vedotin, gemzar plus brentuximab vedotin, bendamustine, and ASCT.Mean duration of everolimus treatment was 5 months (range 4-7). One patient showed complete metabolic remission after 5 months of treatment. This remarkable response was achieved after failure of 6 lines. Partial remission and stable disease each were documented in 40%. Grade 1 neutropenia was reported in 80%. Grade 2 anemia, thrombocytopenia, fatigue and stomatitis were observed in 60%, 80%, 20% and 20% respectively. Everolimus dose reduction (5 mg) was required in two cases (one patient had grade 2 thrombocytopenia and other one had grade 3 fatigue). The latter discontinued the treatment after 4 months and is still in complete remission 5 months after discontinuation. No pulmonary toxicity was observed.Conclusion:The presented data suggest that everolimus is effective in heavily pretreated HL patients who failed conventional treatment including ASCT and new novel agents with 60% ORR. This result is the first of its kind showing efficacy of everolimus after failure of brentuximab vedotin.Literature:Johnston PB et al. A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol. 2010 May;85(5):320-4. DisclosuresNo relevant conflicts of interest to declare.

Magnetically guided delivery of DHA and Fe ions for enhanced cancer therapy based on pH-responsive degradation of DHA-loaded Fe3O4@C@MIL-100(Fe) nanoparticles.

Dihydroartemisinin (DHA) has been investigated in cancer therapy for its reactive oxygen species (ROS) based cytotoxicity originated from interacting with ferrous ions that may reduce or eliminate the multidrug resistance commonly associated with conventional chemotherapy agents. However, synchronously delivery of hydrophobic DHA and Fe (Ⅲ) ions into tumor cells remains a major challenge. In this work, we develop novel Fe3O4@C@MIL-100(Fe) (FCM) nanoparticles for synchronously delivery of DHA and Fe (Ⅲ) for cancer therapy. The MOFs structure based on Fe (Ⅲ) carboxylate materials MIL-100 (Fe) holds great potential for storage/delivery of hydrophobic drug DHA. As a unique nanoplatform, the hybrid inorganic-organic drug delivery vehicles show pH-responsive biodegradation and synchronous releasing of DHA and Fe (Ⅲ) upon reaching tumor sites. The intracellular Fe (Ⅲ) will be reduced further to ferrous ion and interact with DHA to increase its cytotoxicity. The potential of this alternative anti-tumor modality is demonstrated invivo due to an increased intracellular accumulation of DHA in tumor and activated mechanism via co-release of DHA and Fe (Ⅲ), especially under the guidance of an external applied magnetic field.

Antibody Drug Conjugates (ADCs): Changing the Treatment Landscape of Lymphoma

While strides advancing cancer treatment have made it possible to cure some malignancies, the effort to strike an intricate balance between attaining higher efficacy and lower toxicity has been difficult to accomplish, especially with conventional chemotherapy agents. Introduction of antibody drug conjugates (ADCs) has brought us a step closer to this goal and made it possible to target the cancer cells and to minimize effects on normal tissue. Continued efforts have led to approval of two ADCs for cancer therapy, while many others are in various stages of clinical development. The design of ADCs allows them to be internalized into the cancer cells where the drug payload is released and leads to cell death. The key is to identify targets that are exclusively expressed on malignant cells with minimal or no expression on normal cells, which allows for selective killing of tumor cells. Development and approval of more potent ADCs could change the landscape of cancer therapy and possibly eliminate traditional chemotherapy agents from treatment algorithms. In this review, we discuss the ADCs that are being investigated in early and late stage clinical trials for the treatment of B cell non-Hodgkin lymphoma (NHL).

Metastatic renal cell carcinoma imaging evaluation in the era of anti-angiogenic therapies.

During the last decade, the arsenal of anti-angiogenic (AAG) agents used to treat metastatic renal cell carcinoma (RCC) has grown and revolutionized the treatment of metastatic RCC, leading to improved overall survival compared to conventional chemotherapy and traditional immunotherapy agents. AAG agents include inhibitors of vascular endothelial growth factor receptor signaling pathways and mammalian target of rapamycin inhibitors. Both of these classes of targeted agents are considered cytostatic rather than cytotoxic, inducing tumor stabilization rather than marked tumor shrinkage. As a result, decreases in tumor size alone are often minimal and/or occur late in the course of successful AAG therapy, while tumor devascularization is a distinct feature of AAG therapy. In successful AAG therapy, tumor devascularization manifests on computed tomography images as a composite of a decrease in tumor size, a decrease in tumor attenuation, and the development of tumor necrosis. In this article, we review Response Evaluation Criteria in Solid Tumors (RECIST)-the current standard of care for tumor treatment response assessment which is based merely on changes in tumor length-and its assessment of metastatic RCC tumor response in the era of AAG therapies. We then review the features of an ideal tumor imaging biomarker for predicting metastatic RCC response to a particular AAG agent and serving as a longitudinal tumor response assessment tool. Finally, a discussion of the more recently proposed imaging response criteria and new imaging trends in metastatic RCC response assessment will be reviewed.

Melatonin, an inhibitory agent in breast cancer.

The heterogeneous nature of breast cancer makes it one of the most challenging cancers to treat. Due to the stimulatory effect of estrogen in mammary cancer progression, anti-estrogenic agents like melatonin have found their way into breast cancer treatment. Further studies confirmed a reverse correlation between nocturnal melatonin levels and the development of mammary cancer. In this study we reviewed the molecular inhibitory effects of melatonin in breast cancer therapy. To open access the articles, Google scholar and science direct were used as a motor search. We used from valid external and internal databases. To reach the search formula, we determined mean key words like breast cancer, melatonin, cell proliferation and death. To retrieval the related articles, we continuously search the articles from 1984 to 2015. The relevance and the quality of the 480 articles were screened; at least we selected 80 eligible articles about melatonin molecular mechanism in breast cancer. The results showed that melatonin not only inhibits breast cancer cell growth, but also is capable of inhibiting angiogenesis, cancer cell invasion, and telomerase activity. Interestingly this hormone is able to induce apoptosis through the suppression or induction of a wide range of signaling pathways. Moreover, it seems that the concomitant administration of melatonin with other conventional chemotherapy agents had beneficial effects for patients with breast cancer, by alleviating unfavorable effects of those agents and enhancing their efficacy. The broad inhibitory effects of melatonin in breast cancer make it a promising agent and may add it to the list of potential drugs in treatment of this cancer.

Idelalisib for treatment of B-cell malignancies.

The pharmacology, pharmacokinetics, clinical efficacy, safety and tolerability, dosing and administration, and place in therapy of idelalisib, a targeted therapy for certain types of non-Hodgkin's lymphoma (NHL), are reviewed. Historically, conventional cancer chemotherapy agents were recommended for the management of progressive lymphomas requiring systemic treatment; in recent years, however, emerging targeted therapies have altered the landscape of lymphoma treatment. Idelalisib, a novel oral phosphatidylinositol 3-kinase (PI3K) inhibitor, disrupts downstream signaling pathways involved in cancer cell growth and survival. Inhibition of PI3K has been demonstrated to produce durable treatment responses and improved survival outcomes in clinical trials involving patients with indolent forms of NHL. Idelalisib is indicated for use in combination with rituximab for treatment of relapsed chronic lymphocytic leukemia (CLL) and as monotherapy for relapsed small lymphocytic leukemia and follicular lymphoma after the failure of at least two systemic treatments. The recommended dosage of idelalisib is 150 mg orally twice daily; the medication can be taken without regard to mealtimes. The most common adverse effects of idelalisib include diarrhea, nausea, fatigue, cough, and pyrexia. Severe hepatotoxicity and gastrointestinal toxicities, including colitis and intestinal perforation, have also been reported in association with idelalisib use. Ongoing clinical studies are exploring the potential for expanded use of idelalisib in the management of other B-cell malignancies. Idelalisib is a well-tolerated and effective treatment for patients with relapsed or refractory CLL or indolent NHL, providing a novel targeted therapeutic option for the management of these hematologic malignancies.

Brentuximab Vedotin in Pretreated Hodgkin Lymphoma Patients: A Systematic Review and Meta-Analysis

▪Introduction : The outcome of Hodgkin lymphoma (HL) has improved over the past 20 years. However, the probability of relapse after response to initial treatment is currently approximately 10 to 15 percent for localized HL (i.e. stage I and II) and 20 to 40 percent for advanced stages (i.e. IIIB and IV), dependent on prognostic factors [1]. In young patients eligible for dose intensive chemotherapy, salvage chemotherapy with autologous stem cell transplantation (ASCT) is a frequently used therapy option and can be considered as standard [2, 3]. Patients who relapse following ASCT and those not eligible for myeloablative therapy are being treated with conventional chemotherapy or new novel agents such brentuximab vedotin (BV). Since approval of BV several study groups published the results of their experience in treating refractory/relapsed HL patients with BV.Patients and methods: The purpose of this study was to evaluate the impact of BV on outcome of patients with refractory and relapsed HL. In this systematic review we analyzed the published data on refractory / relapsed Hodgkin lymphoma patients who received BV as single agent. A systematic literature search was performed and included studies published from 1st January 2000 to 1st July 2015 in PubMed, electronic databases EMBASE (Dialog), Cochrane Library, DIMDI-Recherche and MEDPILOT. We used the key words brentuximab, brentuximab vedotein, adcetris, CD30 antibody and SGN-35. Recent conference abstracts from the American Society for Clinical Oncology (ASCO) (2012-2015) and American Society of Hematology (ASH) (2012-2014) were also included. Serial reports of 5 patients and more were included. If several publications from same author and group were published, the publications were re-scanned whether the reported patients' cohorts are the same. We included patients treated with BV pre- and post-transplantation as well as those not eligible for transplantation. Publications reporting about experience with BV in several diseases, e.g. T cell lymphoma and HL, underwent special analysis in order to extract only the HL data. Studies using BV in combination with radiation were disqualified for our analysis.Results: 51 out of 5369 screened records met the eligibility criteria. After exclusion of duplicates and serial reports with <5 patients total of 22 records (17 full articles and 5 abstracts) were included. Data of 903 patients treated with BV as salvage treatment was collected. The median age of the cohort was 31 year (range: 26-45). The patients received in median 4 lines (range: 1-9) of chemotherapy prior to BV. Median follow up was 16.1 months (range: 4.5-45.1). Most patients were heavily pretreated, 529/903 and 232/903 underwent high dose chemotherapy and autologous stem transplantation or received allogeneic stem transplantation prior of BV respectively. The response rate was 62.7% (range: 30-100%). The complete remission, partial remission, stable disease and progressive disease rates were 31.8%, 35.1%, 19.5% and 11.7% respectively. The one year progression free survival and estimated one year overall survival were 47.7% and 70% respectively.Conclusion: Significant number of the cohort received autologous and/or allogeneic stem cell transplantation prior BV. Response rate of 62.7% and complete remission rate of 31.8% are supporting results of the pivotal study [4] and establish the solid basis for using BV in heavily pretreated HL patients.Litreature:1. Josting, A., et al., New prognostic score based on treatment outcome of patients with relapsed Hodgkin's lymphoma registered in the database of the German Hodgkin's lymphoma study group. J Clin Oncol, 2002. 20 (1): p. 221-30.2. Sirohi, B., et al., Long-term outcome of autologous stem-cell transplantation in relapsed or refractory Hodgkin's lymphoma. Ann Oncol, 2008. 19 (7): p. 1312-9.3. Rancea, M., et al., High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma. Cochrane Database Syst Rev, 2013. 6: p. CD009411.4. Younes, A., et al., Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol, 2012. 30 (18): p. 2183-9. DisclosuresNo relevant conflicts of interest to declare.

The Importance of Vascular Endothelial Growth Factor as a Marker of Angiogenesis and Lymphangiogenesis in Non-small Cell Lung Cancer

Abstract Lung cancer is the main cause of cancer death both in men and women. In spite of progress seen in the early diagnosis of lung cancer, and implementation of new treatment principles for these patients, 5 year survival of non-small cell lung cancer patients undergoing surgery is low. Introduction of anti-angiogenic therapy administered concomitantly with conventional chemotherapy agents represented practically the first success seen in the treatment of lung cancer in the last 20 years. The aim of this paper is to review the literature informations about the importance of VEGF (vascular endothelial growth factor) as a marker of angiogenesis in patients with non-small cell lung cancer. Therefore, we practiced a literature review about these topics: the importance of VEGF in tumor angiogenesis and lymphangiogenesis in patients with non-small cell lung cancer and his importance as a prognostic factor at these patients, the prognostic impact of serum levels of VEGF and of the cellular expression of VEGF at these patients and also we reviewed the value of the antiangiogenic therapy.

Promises and Challenges of Smac Mimetics as Cancer Therapeutics.

Inhibitor of Apoptosis (IAP) proteins block programmed cell death and are expressed at high levels in various human cancers, thus making them attractive targets for cancer drug development. Second mitochondrial activator of caspases (Smac) mimetics are small-molecule inhibitors that mimic Smac, an endogenous antagonist of IAP proteins. Preclinical studies have shown that Smac mimetics can directly trigger cancer cell death or, even more importantly, sensitize tumor cells for various cytotoxic therapies, including conventional chemotherapy, radiotherapy, or novel agents. Currently, several Smac mimetics are under evaluation in early clinical trials as monotherapy or in rational combinations (i.e., GDC-0917/CUDC-427, LCL161, AT-406/Debio1143, HGS1029, and TL32711/birinapant). This review discusses the promise as well as some challenges at the translational interface of exploiting Smac mimetics as cancer therapeutics.

Minimal Toxicity From Systemic Therapy Given Concurrently With Stereotactic Radiosurgery for Brain Metastases

Chemotherapy is typically not given concurrently with whole brain radiation therapy (WBRT) for treatment of metastatic disease due to increased risk of myelosuppression and neurotoxicity. The goal of this study was to evaluate the prevalence, outcomes, and toxicities of concurrent delivery of systemic therapy with stereotactic radiosurgery (SRS) for treatment of brain metastases. We conducted a retrospective review of 196 patients treated with at least one course of SRS without WBRT for brain metastases between 2009 and 2014. Outcome metrics included the administration of concurrent systemic therapy, grade of myelosuppression, development of neurological symptoms, and overall survival. 196 patients with a median age of 61 years (range, 27-85 years) underwent a total of 290 SRS treatments, with a median of 2 lesions targeted per treatment. Histology included non-small cell lung cancer (40%), melanoma (18%), breast cancer (14%), renal cell cancer (9%), and other (18%). 39% of SRS treatments were delivered concurrently with systemic therapy (i.e. systemic therapy started prior to or during SRS and continued through SRS), of which 51% were with conventional myelosuppressive chemotherapy agents, and 49% were with less-myelosuppressive targeted and hormonal agents. The most common systemic agents included platinum chemotherapies (given with 35% of treatments), ipilimumab (17%), taxanes (16%), pemetrexed (13%), and trastuzumab (13%). Systemic therapy was given during the same week as SRS treatment in 79% of cases. Myelosuppression was minimal in patients treated with both systemic therapy and SRS, with median grade 0 leukopenia, neutropenia, and thrombocytopenia, and grade 1 lymphopenia and anemia over the 1 month following treatment. Grade 3-4 toxicity was minimal (9% of lymphopenia and 3-5% of leukopenia, neutropenia, anemia, and thrombocytopenia) and primarily seen in patients treated with conventional myelosuppressive agents. 52% of patients who received systemic therapy and SRS had neurological symptoms during the 1 month following treatment, and these included fatigue (62%), headache (21%), weakness (15%), and gait instability (15%). Patients treated with myelosuppressive versus non-myelosuppressive agents, as well as systemic therapy given within the same week or not, were equally likely to develop neurological symptoms. Dexamethasone was used in 26% of cases in the month following treatment. Median overall survival for the cohort was 16.9 months following SRS. Systemic therapy can be safely given concurrently with SRS for brain metastases, and this is an attractive option for patients who have both intracranial and extracranial metastatic disease. Our results suggest minimal myelosuppression and neurotoxicity across different systemic agents, even when delivered within the same week as SRS.

Abstract A24: The dual PI3K δ/γ inhibitor, RP6530, in combination with ibrutinib or fludarabine, synergistically enhances cytotoxicity in primary CLL cells in vitro.

Abstract Background: The PI3K pathway is a central pro-survival mechanism in chronic lymphocytic leukemia (CLL). While the delta isoform of PI3K is largely associated with B-cell signaling, gamma is involved in cytokine trafficking and modulation of the tumor microenvironment. Selective pharmacologic targeting of PI3K δ/γ may therefore have therapeutic potential. RP6530 is a novel, potent, and selective PI3K δ/γ inhibitor. RP6530 demonstrates high potency against PI3Kδ (IC50=25 nM) and γ (IC50=33 nM) enzymes with selectivity over α (&amp;gt;300-fold) and β (&amp;gt;100-fold) isoforms. In this study, the potential of RP6530 in inducing primary CLL cell cytotoxicity, both as a single agent and in combination with standard CLL drugs, was assessed. Methods: Blood from treatment-naïve CLL patients seen at the Duke Center for CLL and enrolled in IRB approved protocols at the Duke University and Durham VA Medical Centers was collected. Cells were enriched using Rosette-Sep B cells from Stem Cell Technology, generally giving purity of &amp;gt; 97% of B cells/CLL cells. 2.5 x 105 primary CLL cells were incubated in serum free medium (SFM) with serial dilutions of RP6530, ibrutinib, fludarabine, bendamustine, and chlorambucil, either alone or in combination, in 96 well plates in triplicate. After three days, cytotoxicity was determined using the MTS assay. Fractional cytotoxicity was calculated by comparing absorbance for each experimental condition to absorbance from wells containing CLL cells cultured in SFM alone. For cytotoxicity results of single drugs, a 2-parameter log-logistic model was used to plot the data. For cytotoxicity results of drugs in combination, a 4-parameter log-logistic model was used to plot the data. Modeling and graphing was performed using the drc package in the statistical environment R. Results: The efficacy of RP6530 in CLL lymphocytes collected from five patients was evaluated; 4 with normal FISH cytogenetics, and 1 with 13q deletion. IGHV was mutated in three of the five samples including the one with 13q deletion. Data demonstrate that RP6530 was highly effective at killing primary CLL cells in vitro. Calculated IC50 for RP6530 (362 nM) was lower that the Burton tyrosine kinase inhibitor, Ibrutinib (567 nM), as well the other conventional chemotherapy agents such as fludarabine (14.8 μM), bendamustine (382 μM), and chlorambucil (152 μM). Combination with RP6530 with any of the four other drugs demonstrated potentiation of cytotoxicity. Combination of very low concentrations of ibrutinib and RP6530 (3 nM of each) resulted in a &amp;gt;50% cell kill indicating a dramatic synergistic effect. Likewise, the addition of low concentrations of fludarabine (3 μM) potentiated the cytotoxic effect by causing a 10-fold increase in potency of RP6530 (IC50 = 32 nM). On the other hand, addition of only the higher concentrations of bendamustine (500 μM) or chlorambucil (60 μM) potentiated the cytotoxicity due to RP6530 (IC50 of &amp;lt;3 nM and 60 nM respectively), indicating that the combinatorial effect is most likely to be additive. Conclusions: RP6530 is a potent PI3K δ/γ inhibitor that induces concentration-dependent cytotoxicity in primary CLL lymphocytes both as a single agent as well as in combination with standard CLL therapy. The extreme synergism demonstrated by RP6530 and Ibrutinib even at the lowest concentrations tested warrant evaluation of the efficacy of the combination in CLL patients. Citation Format: Swaroop Vakkalanka, Kumar V. Penmetsa, Dawn Chasse, Youwei Chen, Srikant Viswanadha, Daphne R. Friedman, J Brice Weinberg. The dual PI3K δ/γ inhibitor, RP6530, in combination with ibrutinib or fludarabine, synergistically enhances cytotoxicity in primary CLL cells in vitro. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A24.