bluuebunny/crossref_metadata_2025 huggingface dataset:
Bevacizumab (BEV) use in disseminated choroid plexus papilloma (DCCP).
Authors: Anderson Mark Daniel , Theeler Brett James , Groves Morris D. , Penas-Prado Marta , Yung W. K. Alfred
Published: March 2020

e13039

Background: Choroid plexus papilloma (CCP) is a rare primary neuro-ectodermal tumor of the choroid plexus, representing less than 1% of intracranial tumors in adults. The most common location in adults is the 4th ventricle and treatment is gross total resection (GTR). Leptomeningeal disease (LMD) can rarely occur, even when the tumor retains benign histology. Because of the rarity of DCCP, there is no standard treatment, with less than 20 published cases. There have no previous descriptions of the use of BEV therapy in DCCP. Methods: We present 2 patients (pts) with DCCP, who received gross total resection, radiation and chemotherapy with continued progression, who received treatment with BEV therapy. Results: Pt 1 presented with a 4th ventricular mass and evidence of LMD. GTR of the posterior fossa lesion revealed an atypical CCP. The pt received craniospinal radiation with concurrent temozolomide (TMZ) therapy. After 4 years, there was leptomeningeal disease progression and the pt developed progressive radicular pain and weakness, unresponsive to typical treatments. He was initiated on TMZ and BEV therapy, but the TMZ was discontinued due to thrombocytopenia and the pt was continued on BEV alone. While the MRI showed stable disease at, the pt had complete remission of pain and some improvement of ataxia. When BEV was held due to toxicity, the pain returned until BEV was restarted. Carboplatin was added to BEV with progression of LMD at 21 months. Pt 2 is a 58-year-old man who present with a 4th ventricular mass, shown to be CCP after gross total resection. The pt received radiotherapy for diffuse sacral recurrence. After three years of surveillance, the pt received lomustine and 6-thioguanine for disease progression, limited to 5 cycles by thrombocytopenia. After 5 years, the pt noted continued progressive radicular pain in his lower extremities. The pt completed a planned course of 10 doses of bevacizumab and had improvement in pain control and stable imaging at 11 months. Conclusions: While bevacizumab resulted in stable imaging when used in DCCP, there was significant improvement in debilitating radicular symptoms. The complications of BEV therapy must be considered with the potential benefit of symptomatic relief. Prospective studies are needed.
Phase I study of the combination of BKM120 and bevacizumab in patients with relapsed/refractory glioblastoma multiforme (GBM) or other refractory solid tumors.
Authors: Shih Kent C. , Acs Peter , Burris Howard A. , Hart Lowell L. , Kosloff Rebecca A. , Lamar Ruth E. , Hainsworth John D.
Published: March 2020

e13045

Background: BKM120 is an oral pan-class I PI3 kinase (PI3K) inhibitor, with demonstrated CNS penetration. Enhanced PI3K signaling is common in GBM (56-75% of cases), and is associated with poor survival (Chakravarti et al, 2004). This phase I study was designed to determine the maximum tolerated dose (MTD) of BKM120 in combination with a standard dose of bevacizumab as treatment for patients with relapsed/refractory GBM or other refractory solid tumors. Methods: Patients with relapsed/refractory GBM or other refractory solid tumors for which bevacizumab was an appropriate therapy received BKM120 with bevacizumab in a standard 3+3 dose escalation design. Bevacizumab 10 mg/kg IV was administered days 1 and 15 of 28-day cycles, with escalating doses of BKM 120 self-administered daily. Patients were evaluated for response after 8 weeks; treatment continued until disease progression or unacceptable toxicity. Results: Twelve patients were treated at 2 BKM120 dose levels, DL 1 = 60 mg/day and DL 2 = 80 mg/day. DL 1 (n = 6) tumor types included: 2 GBM, 2 colorectal and 2 NSCLC with treated brain metastases. Dose-limiting toxicity (DLT) of G4 delirium was observed in 1 GBM patient. Three additional patients were enrolled, and no further DLTs occurred. DL 2 (n = 6) tumor types included: 3 GBM and 3 colorectal. DLTs were observed in 2 of 6 patients: 1 colorectal (G3 rash, G3 stomatitis, G3 dehydration, and G2 worsening vomiting), and 1 GBM (G3 ataxia and G3 mental status changes). 6 patients had CNS symptoms possibly related to treatment, including mood alteration (3 GBM and 1 colorectal), delirium, hallucinations, and mental status change (1 GBM patient each). Common treatment-related toxicities (all grades) included: dyspepsia (42%), nausea (33%), ALT elevation (25%), dehydration (25%), proteinuria (25%), rash (25%), and thrombocytopenia (25%). No objective responses were documented; however, 1 colorectal patient remains on treatment with stable disease for 8 months. Conclusions: The addition of BKM120 to standard dose bevacizumab was tolerated at a dose of 60 mg/day. A phase II study with this combination is currently underway in patients with relapsed/refractory GBM. Clinical trial information: NCT01349660.
Anaplastic gliomas: Is there a role for aggressive concomitant treatment?
Authors: Berriel Luiz Gustavo Sueth , Santos Fábio Nasser , Diniz Ana Carolina Sigolo Levy , Chinen Ludmilla Thome , da Costa Alexandre Andre Balieiro Anastacio
Published: March 2020

e13050

Background: Anaplastic glioma is a rare type of glioma, therefore there is no standard treatment after surgery. Adjuvant treatment possibilities are monotherapy with radiotherapy or chemotherapy, or combination therapy done concomitantly or sequentialy. Methods: A comparison of adjuvant treatments in a retrospective analysis of 64 patients with the diagnosis of anaplastic glioma treated at A.C.Camargo Hospital, Sao Paulo-Brazil, from 1994 to 2012. Results: Fifty-eight percent were male, median age 42yo (16-79yo), 76,6% ECOG 0-1, Histopatology was 76,6% astrocytomas, 9,4% oligoastrocytomas and 14% oligodendrogliomas. Adjuvant treatment was concomitant radiochemotherapy in 45, 2%, sequential radiochemotherapy in 14,5%, radiotherapy-only in 16,1%, chemotherary-only in 9,7% and 14,5% received no adjuvant treatment. With a median follow up of 32,2mo (P25-P75 – 13, 3-62, 9mo), median progression free survival (mPFS) was 65mo (CI 29,2 – 100,7mo) and median overall survival (mOS) was 87mo (CI 26,3 – 147,7mo) in the whole group. There was a mOS of 31,4mo for astrocytomas, 89,2mo for oligoastrocytomas and not reached for oligodendrogliomas. Comparing with other treatments, the concomitant therapy group had a longer mPFS (124,8mo vs. 20mo, p: 0,016) and mOS (139,8mo vs. 27,9mo, p = 0.081). When only anaplastic astrocytoma where analyzed, treatment with concomitant radiochemotherapy had better mPFS (p = 0.01) and mOS (p = 0.033). On the other side, treatment with sequential radiochemotherapy didn’t have such impact in either mPFS (p: 0,22) or mOS (p: 0,27). Prognostic factors related with both mPFS and mOS in the whole group were astrocytic histology, multiple lesions and more than 50yo at diagnosis. Non-cortical lesions were also prognostic for mOS. In the multivariate analysis, treatment with concomitant radiochemotherapy had an impact at mPFS (HR 0,28, p = 0.006) and mOS (HR 0,44, p = 0.039). Conclusions: Since there is no standard adjuvant treatment for anaplastic gliomas, evidence for treatment is often taken from GBM studies. This study suggests that an aggressive strategy, like concomitant radiochemotherapy with temozolamide, is useful in grade 3 gliomas, specially in astrocystic histology.
Refining the target area in diffuse gliomas for radiation oncology based upon the location of cingulate gyrus tumors.
Authors: Hamilton Jackson , Matuschek Christiane , Boelke Edwin , Budach Wilfried , Prabhu Sujit S. , Sabel Michael , Butler Brian
Published: March 2020

e13051

Background: Glioblastoma is a brain tumor with poor survival. Radiation therapy (RTX) is often not effective and the target volume could be improved. The aim of this study is to determine if the patterns of spread for cingulate region gliomas could be used to make rational decision for safely altering the treatment planning target volume. Methods: 69 pts. with cingulate gliomas were collected from the collaborating institutions and the patterns of spread were analyzed by serial MRI evaluation. Results: Most pts. present with seizures, one ischemic stroke and one acute hemorrhage was noted. Anterior cingulate was involved in 49 pts. The basal frontal lobe (orbitofrontal or gyrus rectus) was involved in 6 pts. and the insula in 1. There were 20 cases of posterior cingulate involvement including 1 case which wrapped posteriorly from the hippocampus to indusium griseum. None of the cases spread between the anterior and posterior cingulate. 4 had bilateral cingulate involvement. Given that the callosal fibers surround but do not enter the cingulate, the postoperative imaging were assessed which showed that often the callosum was thin and edematous, or had tumor herniate through the callosal isthmus (3 cases), rather than true callosal involvement. Additional cases outside of the 69 pts. showed callosal tumors sparing the cingulate and supra-cingulate frontal and parietal tumors which did not invade the cingulate sulcus. Conclusions: For RTX the areas of cingulate tumor spread which should be considered is the adjacent corpus callosum. There appear to be a relative functional border by the cingulate sulcus and also separating the anterior and posterior cingulate at the level of the paracentral lobules, suggesting the potential for dose deescalation, which may also help with avoiding the supra-cingulate supplemental motor area and leg motor fibers. Other areas to include are the opposite cingulate gyrus, head of the caudate nucleus and septum pellucidum. Anterior cingulate lesions near the genu should include the subcallosal (risky for deficit) and ipsilateral frontal basal areas (risks for frontal lobe syndrome). Sparing the major callosal marginal or pericallosal arteries may help to avoid stroke.
Primary glioblastoma cell lines as source for analysis of the relationship between molecular phenotype and in-vitro drug sensitivity.
Authors: Classen Carl Friedrich , Mullins Christina S , Schubert Julia , Jürgen Piek , Linnebacher Michael , Schneider Björn
Published: March 2020

e13053

Background: Glioblastoma multiforma (GBM) still has a very poor prognosis even with today’s multimodal combination therapy of resection followed by radio-chemotherapy with temozolomide. Both new molecular inhibitors and immunotherapy may represent future therapeutical tools but due to the variability of the molecular composition in individual GBM, they probably depend on better response prediction. Methods: Based on a close cooperation and logistics between surgery, pathology, laboratory researchers and animal care facilities, we established and analysed cell lines of about 30 primary brain tumors, most of them GBM. Tumors and cell lines were characterised by morphology, growth behaviour, numerous extra- and intracellular antigens, and particularly regarding molecular features. Further, tumors were established in a subcutaneous xenograft mouse model, and growth characteristics were described. These in vitro and in vivo models represent an ideal tool for response analysis of single agent or combined treatment in early cell passages in order to predict response. Besides, relevant antigens and possible shifts of antigen-presentation in tumors can be assessed. Numerous analyses using established and new antitumor compounds – e.g. the integrin inhibitor cilengitide – were performed. Results: We found that although the specific integrin expression is individually different in the tumors analysed, cilengitide sensitivity was similar in most. Addition of temozolomide led to additional, yet not over-additive cytotoxicity. In our panel of GBM specimens we found a very heterogenous pattern of molecular alterations, going along with variations of drug sensitivity. Conclusions: This indicates that, in the future field of individualized approaches, such models are required, in order to enable future strategies to predict the efficacy of immunological, small molecular, biological-based, cytotoxic or other therapeutic strategies. The project was supported by the Förderkreis für krebskranke Kinder Rostock e.V., by a Mecklenburg-Vorpommern graduate scholarship, and by a cooperation with Merck-Serono Research and Development (gift of drug).
Phase I dose finding study of AZD8931, an inhibitor of EGFR, HER2, and HER3 signaling, alone or in combination with paclitaxel in Japanese patients.
Authors: Fujisaka Yasuhito , Kurata Takayasu , Tsurutani Junji , Okamoto Wataru , Hayashi Hidetoshi , Kawakami Hisato , Shin Eisei , Hayashi Nobuya , Nakagawa Kazuhiko
Published: March 2020

e13501

Background: AZD8931 is an equipotent, reversible inhibitor of signaling by EGFR, HER2 and HER3. Methods: This open-label, multiple-dose cohort study (NCT01003158) was conducted in Japan to evaluate the safety, tolerability and PK of ascending doses of AZD8931 alone (starting dose 40 mg bd) in patients (pts) with advanced solid malignancies and AZD8931 in combination with paclitaxel (P; 90 mg/m2on days 1, 8 and 15 of a 28-day cycle) in pts with advanced breast cancer. Results: Between Jan 2010 and Apr 2012,17 pts were treated; 11 with AZD8931 monotherapy (40/60/80 mg bd [n=3/4/4]) and 6 with AZD8931 40 mg bd plus P. Median (range) duration of exposure to AZD8931 was 42.5 (22–238) and 79.5 (53–244) days for monotherapy and combination therapy, respectively. No DLTs were observed (in the DLT evaluation period) and therefore the MTD was not confirmed for AZD8931 alone or with P. The most frequent AEs (all grades) with AZD8931 monotherapy were diarrhea, paronychia, rash pustule and dry skin (each n=8) and with combination therapy were diarrhea, stomatitis, rash, alopecia, epistaxis and neutropenia (each n=4). Throughout the study grade ≥3 AEs were reported for 1, 2 and 4 pts in the 40 mg, 60 mg and combination groups, respectively. One serious AE was reported each in the 40 mg (grade 3 intervertebral disc protrusion) and combination (grade 2 infectious pneumonia) groups; neither was considered related to study treatment. One pt in the combination therapy part discontinued due to an AE of grade 1 pneumonia. AZD8931 was rapidly absorbed (median tmax 1–2 hours), well distributed, had moderate clearance (31–39 L/h) and a t½ of 12 hours. There was no suggestion of a PK interaction between AZD8931 and P. One pt on AZD8931 80 mg bd (primary stomach cancer) and another receiving AZD8931 plus P (advanced breast cancer) had an unconfirmed and confirmed PR, respectively (duration of responses 42 and 172 days, respectively) demonstrating preliminary efficacy. Conclusions: Although a MTD was not confirmed for AZD8931, based on overall incidence of AEs of rash and diarrhea in the 80 mg group, doses up to 60 mg bd as monotherapy and 40 mg bd combined with P are the recommended doses for evaluation in Japanese pts. Clinical trial information: NCT01003158.
A phase I study of EMD 525797, a novel humanized monoclonal antibody to human integrin alpha v, in Japanese patients with solid tumor.
Authors: Doi Toshihiko , Fuse Nozomu , Bando Hideaki , Kojima Takashi , Watanabe Morihiro , Yoshino Takayuki , Ohtsu Atsushi
Published: March 2020

e13510

Background: Integrin alpha v, in association with several integrin beta subunits, plays critical roles in migration, invasion, proliferation, and survival of both tumor and endothelial cells and represents an attractive target for cancer treatment. EMD 525797 is a humanized monoclonal IgG2 antibody specifically targeting integrin alpha v. Methods: The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of EMD 525797 were assessed in Japanese patients with advanced solid tumors, treated with intravenous infusions of 250, 500, 1000, or 1500 mg of EMD 525797 (given over 1 h), who received 3 doses (weeks 1, 3, and 5) before response assessment during week 6. Thereafter, patients without progressive disease could receive further doses every 2 weeks. Dose-limiting toxicities (DLTs) were assessed over the first 4 weeks and safety was monitored until 31 days after the last administration of EMD 525797. Results: A total of 27 patients were treated. Regarding the primary site of disease, 17 patients had colorectal cancer, 3 pancreatic cancer, 2 gastrointestinal stromal tumors (GIST), 1 esophageal cancer, 1 gastric cancer, 1 rectal carcinoid, 1 cholangiocarcinoma, 1 hepatocellular carcinoma, and 1 leiomyosarcoma. Twenty-five patients (92.6%) experienced treatment-emergent adverse events (TEAEs); nausea (25.9%), headache (22.2%), pyrexia (22.2%), stomatitis (22.2%), and vomiting (22.2%) were the most common. None of these TEAEs was greater than grade 3 by NCI-CTCAE version 4.0 and no DLT was observed. Fourteen (51.9%) of the TEAEs were possibly related to EMD 525797. Two patients, 1 with GIST and 1 with rectal carcinoid, had longer than expected exposure time (>84 days). EMD 525797 showed a non-linear PK profile. Distribution volume and clearance after EMD 525797 administration did not show apparent ethnic difference considering body weight influence. Conclusions: EMD 525797 was well tolerated in Japanese patients. The safety profile in Japanese patients was comparable to the results from Caucasian patients. In some patients EMD 525797 treatment duration was longer than expected. Clinical trial information: NCT01327313.
Induction of autophagy across multiple tumor types through irreversible HER tyrosine kinase blockade.
Authors: Gwin William Rayford , Liu Leihua , Zhao Sumin , Xia Wenle , Spector Neil
Published: March 2020

e13517

Background: Human epidermal growth factor receptor (HER) receptor tyrosine kinases play a key role in solid tumor oncogenesis. Despite broad expression of HER receptors in solid tumors, HER targeted therapies have not shown significant improvement in survival, calling into question the value of wild-type HER receptors as therapeutic targets. Here we found that an irreversible pan-HER tyrosine kinase inhibitor (TKI), neratinib, but not similar HER TKIs, induced morphologic changes in ovarian, TNBC, and prostate cancer cell lines consistent with induction of autophagy. Methods: SKOV3 (ovarian), OVCAR8 (ovarian), HBL-100 (TNBC), and LAPC4 (prostate) cancer cells were treated with lapatinib, gefitinib, CI-1033, afatinib, and neratinib (0.5mM-2.5mM). The activation state of HER2, EGFR, HER3, Akt, Erk, p70S6, 4EBP1, and Ulk1 was determined by Western blot analysis (WB) at various time points of neratinib treatment. LC3 was analyzed by immunofluorescence (IF) microscopy and WB. Analysis of proliferation, apoptosis, and cell cycle were performed using WST-1, annexin V, and PI staining, respectively. Results: Neratinib, but not similar HER TKIs, induced marked cytoplasmic vacuolization in tumors. The conversion of LC3-I to LC3-II in neratinib-treated cells was consistent with induction of autophagy. Moreover, PI3K/Akt, MAPK/Erk1/2 and mTORC1 signaling cascades were inhibited in neratinib-treated cells, and were associated with the inhibition of phospho-Ulk1, a key step in autophagy initiation. Treatment with neratinib alone resulted in G1 cell cycle arrest. Importantly, the combination of neratinib and chloroquine, an autophagy inhibitor, induced a statistically significant inhibition of cellular proliferation (p <0.01) and increased apoptosis compared to treatment with either drug alone. Conclusions: Our data suggest that more effective inhibition of wild-type HER receptors, can lead to mTORC1 inhibition, which in turn triggers autophagy. Here, autophagy appears to protect cells rather than inducing apoptosis. Consequently, targeting both HER receptors and autophagy represents an attractive therapeutic strategy to treat tumors expressing wild-type HER receptors.
BEZ235 in combination with everolimus for advanced solid malignancies: Preliminary results of a phase Ib dose-escalation study.
Authors: Salkeni Mohamad Adham , Rixe Olivier , Abdel Karim Nagla , Ogara Sue , Feiler Monica , Moorthy Ganesh , Mercer Carol A , Thomas Hala , Desai Pankaj B , Fathallah Hassana , Kozma Sara , Thomas George , Morris John Charles
Published: March 2020

e13518

Background: The mammalian target of rapamycin (mTOR) is a critical signaling pathway in many tumors including cancers of the breast and colon, glioblastoma multiforme, and hepatocellular carcinoma (HCC). Preclinical studies demonstrated the combination of BEZ235, a competitive dual phosphatidylinositide 3-kinase (PI3K)/mTOR inhibitor, and the mTOR inhibitor, everolimus led to greater regression of a carcinogen-induced HCC than treatment with higher doses of either drug alone. Based on this, we initiated a study of BEZ235 combined with everolimus in patients with advanced solid tumors. Methods: A single institution phase Ib dose-escalation study. Patients with advanced solid malignancies, no available standard of care treatment option, and ECOG performance status 0-2 were eligible. Prior treatment with PI3K inhibitors was not allowed. Sequential cohorts of 3-6 patients were treated. The starting dose was everolimus 2.5 mg and BEZ235 200 mg daily in an oral sachet formulation. Cohort 2 received everolimus 2.5 mg and BEZ235 400 mg daily. Pharmacokinetic and pharmacodynamic studies were performed during the first cycle. The phosphorylation of specific downstream effectors of the mTOR pathway was assessed in peripheral blood mononuclear cells (PBMC). Results: Eleven patients, median age 58 (36-73 years) were treated. Tumors included non-small cell lung cancer, colon cancer, and glioblastoma, hepatocellular carcinoma, pancreatic cancer, esophageal cancer, adenoid cystic carcinoma of the larynx, and appendiceal carcinoma. Four patients were treated on cohort 1. None experienced dose-limiting toxicity. Seven patients were treated on the second dose cohort. One patient withdrew necessitating replacement and another developed grade 3 stomatitis from herpes virus requiring cohort expansion. The most common adverse events were thrombocytopenia, lymphopenia, transaminitis, diarrhea, nausea and fatigue. No tumor responses were noted. PBMC showed a decrease in 4E-BP1S65 phosphorylation on day 28 in 2 of 3 patients in cohort 1. Conclusions: The combination of BEZ235 and everolimus was well tolerated at these doses. The trial remains open to accrual. Clinical trial information: NCT01508104.
Phase I expansion study of sunitinib and bevacizumab in patients with advanced solid malignancies.
Authors: Mittal Kriti , Koon Henry B. , Elson Paul , Triozzi Pierre L. , Dowlati Afshin , Borden Ernest C. , Rini Brian I.
Published: March 2020

e13521

Background: The vascular endothelial growth factor (VEGF) antibody bevacizumab (Bev) and the VEGF receptor (VEGFR) inhibitor sunitinib are efficacious agents in many malignancies. This combination has been previously evaluated in phase I studies of advanced solid tumors. In addition to renal cell carcinoma (RCC), objective responses in the previous phase I occurred in melanoma and adrenal carcinoma. An expansion phase of the phase I study was undertaken primarily to obtain further safety data in these tumor types. Methods: Patients (pts) with metastatic solid tumors with ECOG performance status 0-1 were enrolled on a phase I trial of sunitinib (37.5 mg daily weeks 1-4) and Bev (5 mg/kg iv on days 1, 15 and 29) of a 6 week cycle. Responses were assessed by CT scans performed at baseline and every 12 weeks based on RECIST criteria v1.0. Results: Twenty-two pts were enrolled (10 males, 12 females; median age 58 years) in the expansion cohort. Tumor types included melanoma (11), RCC (5), adrenal cancer (5) and angiosarcoma (1). Prior systemic treatment included chemotherapy (41%) and immunotherapy (27%). Common all grade toxicities included fatigue (77%), hypertension (73%), thrombocytopenia (68%), nausea (59%) and oral mucositis (55%). Grade 3 or higher toxicities occurred in 15 pts (68%); including hypertension (41%), thrombocytopenia (23%) and fatigue (14%). Seven pts developed hemorrhagic events, all grade 1 or 2. Two pts experienced grade 4 thrombocytopenia, 3 RCC pts developed grade 1 thrombotic microangiopathy (TMA); while 1 melanoma patient developed decreased haptoglobin (grade 1) with associated thrombocytopenia (grade 4) and schistocytes consistent with TMA. A median of 2 cycles were completed (range, 1-8). Best response in 19 evaluable pts included partial response 21% (4/19; melanoma (2), adrenal (1), and RCC(1)); stable disease 21% (4/19) and progressive disease 58% (11/19). Overall, 6 pts (31.5%) had measurable reduction in tumor burden. Conclusions: The safety profile of Bev plus sunitinib in melanoma and adrenal carcinoma pts is similar to the previously evaluated toxicities in RCC pts. Although reversible, combined VEGF and VEGFR inhibition may lead to microangiopathy even in non-RCC pts. Clinical trial information: NCT00357318.
Effect of ABTL0812, a safe dual inhibitor of mTORC1/C2 and dihydrofolate reductase, on gemcitabine and docetaxel cytotoxicity in pancreatic and lung cancer cells.
Authors: Alfon Jose , Espadaler Jordi , Garcia Jose A , Domenech Carles , Lizcano Jose M
Published: March 2020

e13526

Background: We have previously described that ABTL0812 has oral anticancer properties. The action is exerted through a mechanism of action involving the inhibition of mTORC1 and mTORC2 (mammalian target of rapamycin) pathways and dihydrofolate reductase (DHFR) expression. Administration of ABTL0812 reduced tumor volume similarly or more than standards of care (SOC) in A549 or MiaPaca2 xenografts in mice. Moreover, a 28-day rat toxicity study has shown very low toxicity (NOAEL=500 mg/Kg) good bioavailability and pharmacokinetic linearity, suggesting a broad therapeutic window. A FiM phase I clinical trial in patients with advanced cancer is scheduled to start in June 2013. Methods: Cellular assays were performed in A549 lung adenocarcinoma, and MiaPaca-2 pancreatic carcinoma cells. Cell proliferation was carried out by bromodeoxyuridine (BrdU) incorporation, cell viability by MTT, and protein expression and phosphorylation by immunoblotting. Cellular apoptosis was assessed both by caspase 3 immunoblot and Hoechst 3342 nuclear staining and quantification of nuclei; and autophagy by LC3-II lipidation assay in immunoblots. All studies were performed with ABTL0812 either alone or in combination with SOC. Results: ABTL0812 potentiated the cytotoxic effects of gemcitabine and docetaxel in MiaPaCa-2 and A549 cancer cells, respectively. In MTT assays, the IC50’s of gemcitabine and docetaxel decreased 7 and 80 times in MiaPaca-2 and A549 cells, respectively, when cells were co-incubated with non-cytotoxic ABTL0812 concentrations. Analysis of the activity (Chou and Talalay’s method) revealed that ABTL0812 synergizes with gemcitabine and docetaxel to promote cytotoxicity. We also present data showing the effects of gemcitabine and docetaxel on the molecular targets of ABTL0812 such as Akt and ribosomal S6 phosphorylation, DHFR expression and cellular autophagy. Conversely, we also show the effects of ABTL0182 on cellular apoptosis induced by gemcitabine and docetaxel. Conclusions: ABTL0812 synergistically potentiates the cytotoxic effect of gemcitabine and docetaxel in pancreatic and lung cancer cell models.
Outcome analyses of patients with metastatic cervical cancers in a phase I clinic.
Authors: Hou Ming-Mou , Liu Xiaochun , Wheler Jennifer J. , Naing Aung , Hong David S. , Bodurka Diane C. , Schmeler Kathleen M. , Tsimberidou Apostolia Maria , Janku Filip , Zinner Ralph , Piha-Paul Sarina Anne , Lu Karen H. , Wolff Robert A. , Kurzrock Razelle , Fu Siqing
Published: March 2020

e13534

Background: Patients with metastatic cervical cancers have a poor prognosis and few effective therapies available. Thus, access to a phase I trial may provide a viable option. Methods: Outcomes of 54 consecutive patients with metastatic cervical cancers seen in a phase I clinic at MD Anderson Cancer Center from 1/1/2006 to 12/31/2012 were reviewed in accordance with the MD Anderson IRB guidelines. Results: The 54 patients included Caucasians (n=34, 63%), Hispanics (n=9, 17%), African Americans (n=7, 13%), and others (n=4, 7%). Pathological diagnoses were squamous cell carcinoma (n=33, 60%), adenocarcinoma (n=12, 22%), adenosquamous (n=3, 6%), poorly differentiated carcinoma (n=2, 4%), small cell carcinoma (n=2, 4%), clear cell carcinoma (n=1, 2%), and melanoma (n=1, 2%). Initial staging was as follows: I (n=16, 30%), II (n=11, 20%), III (n=11, 20%), and IV (n=16, 30%). Prior treatment included surgery (n=23, 43%), radiotherapy (n=41, 76%), and systemic chemotherapy (n=54, 100%) including one regimen (n=30, 55%), two (n=15, 28%) and more (n=9, 17%). At their initial visit to the phase I clinic, the median age was 47 years. The majority of patients had ECOG PS 0-1 (n=45, 83%), and MDACC prognostic scores 0-1 (n=48, 89%). Almost all the 54 referred patients were enrolled into a phase I trial (n=52, 96%). Initial phase I trials these patients had received led to one CR, five PR, and 12 SD ≥ 6 months (CR/PR/SD≥6 months=35%). Of the patients who progressed on their first protocols, 11 patients (21%) were enrolled into a second protocol, leading to 36% of PR/SD≥6 months (n=4). Among those enrolled into a third (n=4) and a fourth (n=1) study, no CR/PR/SD≥6 months was achieved. The median overall survival in these 54 referred patients was 10.6 months. Among 36 patients who underwent molecular marker studies, 15 were found to harbor PIK3CA mutations and/or PTEN loss (42%) and achieved 60% of CR/PR/SD≥6 months (3 PR and 6 SD≥6 months). Conclusions: Aberrant PI3K pathway was frequently identified in advanced cervical cancers, and the high rate of CR/PR/SD≥6 months was observed in these patients treated under a phase I trial, suggesting that phase I trials, especially mutation matched regimens, may provide potential benefits to these patients.
DNA repair suppression and effect of cisplatin in mesothelioma and lung cancer cell lines.
Authors: Røe Oluf D. , Chen Wu , Zhi Xiaofei , Chen Duan , Chen Yijiang
Published: March 2020

e13542

Background: Recently we characterized a gene profile with overexpressed DNA double strand repair systems in mesothelioma versus normal tissue, where homologous recombination (HR) and non-homologous end joining (NHEJ) were prominent systems overexpressed. They play a role in resistance to the DNA damaging agent cisplatin, the backbone of both mesothelioma and lung cancer treatment. We hypothesized that inhibition of these systems could increase the effect of cisplatin. Methods: Cisplatin and two natural compounds A and B inhibiting HR and NHEJ respectively were tested as single treatment and various combinations in mesothelioma (MSTO-211H), parental (A549) and cisplatin resistant lung cancer cells (A549/DDP) were the dose-response and time-response was determined. Sterile MTT (0.5mg/ml) was added at 37°C for 4h, then removed and DMSO added for 10 minutes. Spectrometric absorbance at 570nm was measured. The inhibition rate was calculated by the relative inhibition curve. The IC30 doses of cisplatin was combined with IC5 of the experimental compounds to reveal the effects of combining chemotherapy with non-toxic compounds. Results: The IC5 of the experimental compounds A and B were 2μM and 1mM in the MSTO-211H and A549 respectively, and similarly in the A549/DDP cells, 2μM and 0.5mM. The IC30 of cisplatin was 1,5 μg/ml in the MSTO and A549 and 20 μg/ml (13-fold) in the A549/DDP cells.The combination of IC5 of A and B without cisplatin showed a synergic effect of about 50%. IC30 of cisplatin from 24h to 72h without pretreatment showed 20% inhibition at 48h and interestingly the inhibition rate was reduced to 10% at 72h. Pretreatment with A and B for 24h, and then cisplatin for 48h had the same effect as cisplatin together with A and B for 48h, about 30% inhibition. Pretreatment with A and B for 24h, then addition of cisplatin plus A and B for 48h had the strongest effect of >50% inhibition rate. Conclusions: Our results indicate that suppression of HR and NHEJ in both mesothelioma and non-small cell lung cancer cell lines by non-toxic doses increased cisplatin efficacy. The acquired cisplatin resistant A549/DDP remained sensitive to the natural inhibitors. Molecular analyses on DNA damage and apoptosis will be presented at the meeting.
New targeted anti CDK4/6 peptide MM-D37K.
Authors: Bozhenko Vladimir Konstantinovich , Kulinich Tatyana Michailovna , Kudinova Elena Aleksandrovna , Boldyrev Andrey , Solodkij Vladimir Alekseevich
Published: March 2020

e13545

Background: MM-D37K is a synthetic peptide which consists of p16INK4a-specific inhibitor of complex cyclin D- CDK4 and CDK6 and cell penetrating peptide (CPP) – Antp (Penetratin). We investigated in vitro and in vivo cytotoxic, cytostatic and antitumor activity of MM-D37K. The level of cyclin A, Ki67,bax, bcl-2 and pRb phosphorylation was investigated. Full range of Toxicology tests and Pharmacokinetics experiments in mice, rats and rabbits were performed. Methods: Different cell lines (Jurcat, Raji, A549, MCF-7, Hct-116, Ht-29, HEK293) were incubated with 0.1-100 mM MM-D37K for 24-48 hrs. Proliferation (MTT), DNA-content, cell cycle (flow cytometry) and mRNA level of appropriate proteins (RT PCR) were investigated. In vivo experiments were conducted on xenograft model of HCT116, A-549 at concentration 5 and 10 mg/kg of MM-D37K. Toxicology experiments were made under RF Law and included 3 types of animals. LC-MS MMD37K method of detection in plasma was developed. Results: MM-D37K prevented pRb phosphorilation and proliferation activation in all investigated cell lines. Cell cycle was blocked in G1 phase. Cytostatic effect did not depend on p16 mutation or expression. MM-D37K induced apoptosis in 20-82% of investigated cells at 40 mM with lowest level for MCF-7. LD10 for rats was 100 mg/kg and no deaths were registered for rabbits (highest dose was 50 mg/kg). Concentration of MMD-37K in plasma after 2 min and bolus i.v. injection in dose 10 mg/kg was 72.16±5.64 mcg/ml. Concentration decreased in two phases. 1st – t1/2 = 2.39±0.39 min and for 2nd t1/2=2.39±0.39 hr. Antitumor effects in xenograft model were 53% for A-549 and 67% for HCT116. Conclusions: Our results proved cytotoxic, cytostatic and antitumor effects of MM-D37K in investigated cell lines in vitro and in vivo. Toxicological and pharmacokinetics results allow us recommend for I/IIa Phase clinical trial. (Support: MetaMax Ltd., RFFI, Minpromtorg RF.)
Genetic susceptibility to toxicity of chemotherapy in mice as pharmacokinetics-independent and drug-specific.
Authors: Dittmar Ashley J , Affronti Hayley , Sepporta Maria Vittoria , Gebuijs Elizabeth , Demant Peter
Published: March 2020

e13549

Background: Adverse drug reactions (ADRs) are a significant obstacle in cancer chemotherapy. In spite of the advances in the development of drugs for cancer therapy, ADRs compromise their potential beneficial effects in many patients by imposing reduction of dose or cessation of treatment. Prediction of susceptibility to ADRs in individual patients could significantly improve treatment outcomes by more effectively choosing which drugs to treat with and which dose is appropriate. The pharmacokinetics (PK) of many drugs has been extensively studied and numerous enzymes and transporters that are involved in their activation and processing have been identified. However, when their role in individual susceptibility to ADRs has been tested in numerous studies, the variants of these proteins have not been able to consistently predict specific ADRs. Therefore, additional studies are required for a reliable prediction of toxicity. Methods: We used mouse strains with precisely defined limited genomic differences to evaluate genetic control of ADRs to three drugs commonly used in cancer chemotherapy - irinotecan, gemcitabine, and doxorubicin. We compared strain distribution of susceptibility to ADRs caused by each of these drugs and tested whether there is a correlation with genotypes at the major processing/transport (PK) genes that were reported in humans to affect toxicity of these drugs. Results: The major genetic differences in toxic reactions caused by these drugs do not correlate with the major PK loci and that the strain distribution pattern of susceptibility vs. resistance for each drug is different. Conclusions: This data suggests that a significant part of genetic susceptibility to ADRs is controlled by genes other than the presently known PK-related genes, and that many responsible genes are drug specific, with some possible overlaps. We hypothesize that these genes are likely involved in downstream pharmacodynamic (PD) processes and have remained largely unknown, because most studies in humans have been limited to known PK-related genes. We are proceeding towards identification of these novel genes, as they could help to optimize the selection of therapy for individual patients.
Cytotoxic effect of euphol from Euphorbia tirucalli on a large panel of human cancer cell lines.
Authors: Reis Rui Manuel , Silva Viviane Aline Oliveira , Rosa Marcela Nunes , Tansini Aline , Lima Joao Paulo Da S.N. , Jones Chris , Pianowski Luiz Francisco
Published: March 2020

e13557

Background: The tetracyclic triterpene alcohol euphol is the main constituent found in the sap of Euphorbia tirucalli. In Brazil its latex is used as anticancer and other diseaseas folk treatment, yet, little is known about its anticancer proprieties. We aimed to study the antitumor effect of euphol on a large panel of human cancer cell lines. Methods: Anti-tumor effects of euphol in vitro were assessed using MTS assays on 77 human cancer lines from13 solid tumor models, such as breast, colon, bladder, prostate, lung, pancreas, esophagus, glioblastoma, melanoma, head and neck and cervical cancer. Additionally, we evaluate the its potential combinatorial value with temozolomide in gliomas. Ongoing experiments will identify potential drug target(s) by assessing changes in global protein expression. Results: Euphol exhibited dose and time-dependent cytotoxic effects on all cancer cell lines analyzed. Among each tumor type, the distinct cell line exhibited a heterogeneous profile of response to euphol. Esophageal squamous cell carcinoma and pancreatic carcinomas showed the most sensitive profile. In comparison with temozolomide, euphol showed a median of 30 fold higher efficacy, range 5-167 fold, in the glioma cell lines analyzed (Table). Conclusions: Euphol demonstrated potent anti-tumor activity on the majority of cancer cell lines evaluated. Our findings may provide insight into the tailoring designing of euphol-based therapies for cancer patients. [Table: see text]
Targeting the PI3K signaling cascade in PIK3CA mutated endometrial cancer in a primary human xenograft model.
Authors: Bradford Leslie Siriya , Rauh-Hain Jose Alejandro , Clark Rachel Marie , Groeneweg Jolijn W , Zhang Ling , DiGloria Celeste M , Borger Darrell R. , Growdon Whitfield Board , Schorge John O. , Foster Rosemary , Rueda Bo R
Published: March 2020

e13564

Background: Alterations in the PI3K pathway are highly prevalent in endometrial cancer due to PIK3CA mutation and loss of PTEN. Given these data, we investigated the anti-tumor activity of the PI3K inhibitor NVP-BKM120 (BKM) as a single agent and in combination with standard cytotoxic chemotherapy in a human primary endometrial xenograft model. Methods: NOD/SCID mice bearing xenografts of primary human tumors with and without PIK3CA gene mutations were randomly divided into two- and four-arm cohorts with equivalent tumor volumes. Three single agent experiments tested the effectiveness of NVP-BKM120 against two endometrioid (PIK3CA wild type and H1047L mutant) and one carcinosarcoma (PIK3CA R88Q mutant) endometrial cancer. Three four arm experiments tested NVP-BKM120 alone and in combination with paclitaxel and carboplatin (P/C) in two endometrioid tumors (both R88Q) and one carcinosarcoma (no PIK3CA mutation detected). Following in vivo study, tumors from the NVP-BKM120 , P/C, P/C+ NVP-BKM120 and vehicle treated mice were processed for determination of PI3K/AKT/mTOR pathway activation. Wilcoxan rank sum analysis was utilized to compare tumor growth across all treatment experiments. Results: In endometrioid single agent experiments, NVP-BKM120 resulted in tumor growth suppression starting at days 5-10 compared to the linear growth observed in vehicle treated tumors (p<0.04 in all experiments). In all experiments, tumor resurgence manifested between days 14-25 (p<0.03). When combined with P/C, the NVP-BKM120 resistance pattern failed to develop in all three xenograft lines (p<0.05) while synergistic tumor growth suppression (p< 0.05) of only one xenograft tumor harboring the R88Q mutation was observed. Acute treatment with NVP-BKM120 led to a decrease in pAKT, whereas, there was no difference in pAKT levels following chronic therapy compared to vehicle. Conclusions: These data suggest that NVP-BKM120 mediated inhibition of the PI3K pathway in endometrial tumors with and without a PIK3CA mutation precludes tumor growth in a primary xenograft model. While a pattern of resistance emerges, this effect appears to be mitigated by the addition of conventional cytotoxic chemotherapy.
Effect of pan-PI3K and HER2 blockade on antitumor activity in preclinical models of breast cancer resistance to trastuzumab therapy.
Authors: De Pradip , Sun Yuliang , Friedman Lori , Dey Nandini , Leyland-Jones Brian
Published: March 2020

e13570

Background: PI3K-AKT-mTOR pathway signaling is important for the oncogenic function of HER2. Activating alterations of this pathway are frequently observed in HER2-enriched breast cancer and generally herald a poor response and resistance to trastuzumab (T). Targeting the PI3K-AKT-mTOR pathway is an attractive strategy in HER2+ breast cancer that is refractory to trastuzumab. The hypothesis is that the suppression of this pathway by pan-PI3K inhibitor, GDC-0941 may lead to overcome trastuzumab-resistance. Methods: The antiproliferative and HER2-mediated cellular signaling (pAKT, pP70S6K, pS6RP, p4EBP1 and p-ERK) effects of GDC-0941 alone and in combination with T were evaluated in HER2 amplified T-sensitive (BT474), T-resistant (BT474HR), and HER2 amplified/PIK3CA mutated (HCC1954, UACC893) BT cell lines by MTT assay and Western blots. Athymic mice bearing BT474 and BT474HR xenograft tumors were treated with GDC-0941 and T (alone and in combination). Results: (1) GDC-0941 exhibited in vitro cell killing activity in MTT assay with IC50’s ranging from 0.35 µM to 1 µm and potency was augmented by the addition of T, (2) inhibition of phosphorylation of AKT(S473, T308), P70S6K, S6RP, and 4EBP1(T37/46, T70) was observed following GDC-0941 treatment, and the combination of GDC-0941 and T more effectively blocked the PI3K-AKT-mTOR pathway, (4) GDC-0941 dose-dependently blocked 3D-ON-TOP clonogenic growth of HER2+ cells. This effect was potentiated in the presence of T and (5) xenograft data show that the combination of GDC-0941 and T has strongly enhanced anti-tumor effect in both sensitive (82%) and resistant models (79%), something that cannot be achieved by either monotherapy. Conclusions: Our data suggest that 1) therapeutic targeting of the PI3K-AKT-mTOR signaling should be effective in abrogating resistance to T therapy in HER2+ BT, and 2) targeting both the HER2 and the PI3K signaling pathways is an attractive strategy to enhance the clinical activity of T therapy, as well as to prevent or delay the development of resistance.
Pharmacokinetic study of aldoxorubicin in solid tumor patients.
Authors: Natale Ronald B. , Mita Alain C. , Wolin Edward M. , Laabs Brenda , Dinh Hillary , Wieland Scott , Levitt Daniel , Mita Monica M.
Published: March 2020

e13572

Background: Aldoxorubicin consists of doxorubicin conjugated to a pH sensitive linker that binds covalently to circulating albumin. Previous studies demonstrated that aldoxorubicin can be administered at doses up to 350 mg/m2 (260 mg/m2doxorubicin equivalents, DE) every 21 days for up to 8 cycles. We have investigated aldoxorubicin pharmacokinetics, including albumin-bound and free doxorubicin and doxorubicinol after administration of 2 dose levels of aldoxorubicin in patients with advanced solid tumors. Methods: Patients with solid tumors and no standard therapy were eligible. Other entry criteria: ECOG PS 0-2, LVEF > 45% of predicted normal for the site, adequate hematological status. Patients were administered either 230 mg/m2 aldoxorubicin (165 mg/m2 DE) or 350 mg/m2 aldoxorubicin (260 mg/m2 DE) iv over 30 minutes on day 1 of cycles 1 and 3. Blood samples were taken prior to administration and at multiple time points up to 72 hr post administration. Serum concentrations of albumin-bound doxorubicin, unbound doxorubicin and doxorubicinol were analyzed. Results: As of January 31, 7 subjects have been entered in the study. 6 subjects have received 230 mg/m2 aldoxorubicin and 1 subject has received 350 mg/m2 aldoxorubicin. No serious adverse events have been reported. Grade 3 or 4 adverse events include neutropenia, thrombocytopenia and anemia. A minor response (20% decrease) was observed in one subject (230 mg/m2aldoxorubicin) with small cell lung cancer who had received 3 prior chemotherapy regimens. For the 230 mg/m2 cohort during cycle 1, median results for albumin-bound doxorubicin include Cmax= 64 µg/mL, tmax= 0.25 hr, t1/2= 19.7 hr, AUC t-∞= 1500 h*µg/mL, CLpred= 0.153 L/h/m2, Vss pred= 3.91 L/m2. Results were similar for cycle 3. Free doxorubicin accounted for only 0.8% of total doxorubicin detected, and doxorubicinol less than 0.0007% of total drug. Results from the 350 mg/m2 cohort are pending. Data from all 12 subjects will be available at presentation. Conclusions: Aldoxorubicin binds rapidly to albumin and is cleared slowly from the circulation. It possess a relatively narrow volume of distribution. These characteristics distinguish aldoxorubicin from published PK data for doxorubicin. Clinical trial information: NCT01706835.
Risk of pneumonitis with mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus.
Authors: Ranpura Vishal Navnitray , Wu Shenhong
Published: March 2020

e13573

Background: Pneumonitis is associated with the use of mTOR inhibitors, everolimus and temsirolimus, which have been used widely in cancer therapeutics and clinical trials. Currently, the overall risk of pneumonits in patients treated with mTOR inhibitors has not been defined. We performed a systematic review and meta-analysis of published clinical trials to assess the risk of pneumonitis in cancer patients treated with mTOR inhibitors. Methods: Databases from PUBMED, the Web of Science, and abstracts presented at the American Society of Clinical Oncology conferences until May 2012 were searched to identify relevant studies. Eligible studies included prospective clinical trials in which patients received treatment with everolimus or temsirolimus as a single agent or in combination with other agents. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated employing a fixed- or random-effects model based upon the heterogeneity of the included studies. Results: A total of 2,303 patients with a variety of tumors from 18 studies (everolimus: 12, temsirolimus: 6) were included for the analysis. The overall incidences of all-grade and high-grade pneumonitis with mTOR inhibitors were 6.5% (95% CI: 3.7-11.1%) and 2.5% (95% CI 1.2-5.4%) respectively. The risk of all-grade pneumonitis did not vary significantly with tumor types (P=0.079), but vary significantly with their combination with other agents (P<0.001). There was no significant difference between everolimus and temsirolimus in the incidence of all-grade (P=0.22) and high-grade (P=0.28) pneumonitis. In comparison with controls, mTOR inhibitors significantly increased the risk of all-grade (RR=5.2, 95% CI: 2.09-12.93, P<0.001) but not high-grade pneumonits (RR=2.63, 95% CI: 0.66-10.40, P=0.41). Conclusions: The risk of pneumonitis is increased in cancer patients receiving mTOR inhibitors without significant difference between everolimus and temsirolimus.