bluuebunny/crossref_metadata_2025 huggingface dataset:
A study of denileukin diftitox to treat refractory ovarian cancer.
Authors: Czerlanis Cheryl M. , Drakes Maureen , Elmishad Amira , Kosik Kelly , Parthasarathy Mala , Potkul Ronald , Smith Donna M. , Yu Zheng , Zakrzewski Sandra , Stiff Patrick J.
Published: March 2020

e13121

Background: The number of circulating CD4+ regulatory T-cells (Tregs) has been correlated with outcome in advanced ovarian cancer. A prior report (Barnett, et al; AACR Abstracts 2006: 1148) suggested that denileukin diftitox, a fusion toxin containing interleukin-2 fused to diphtheria toxin, may be of therapeutic value in this disease acting via Treg depletion. As part of a larger study of denileukin diftitox with dendritic cell-based vaccination, we treated patients with the agent alone to determine if it depletes circulating CD4+CD25HiFoxP3+CD127Low Tregs and induces clinical responses. Methods: Patients with relapsed/refractory ovarian or primary peritoneal carcinoma were eligible. No chemotherapy or immunotherapy was allowed for the preceding 4 weeks. Denileukin diftitox 18 μg/kg IV was given every 28 days for up to 4 cycles. Weekly monitoring of CD4 Tregs and CD8+CD28- Tregs was done by monoclonal antibody labeling of PBMC and flow cytometry studies. Clinical responses were measured by standard methods of disease assessment including CA125 testing. Results: Seven women were treated, of whom 3 had minimal residual disease (MRD). No Grade III-IV toxicities were seen. Unlike the prior report, no clinical responses were seen in 4 patients with bulky measurable disease. Median progression free survival was 5.5 months (range 0.5-20.5) and median overall survival will exceed 21.6 months (range 1.4-26.5+) with MRD a marker for prolonged remissions and survival. We saw no Treg depletion after the 1st cycle; i.e., no patient had ≥25% reduction in Tregs at the expected nadir at day 14. Mean CD4+CD25HiFoxP3+CD127Low Tregs/CD4 cells for controls was 1.16% (range .35-2.13) at baseline, with no significant temporal variation. Mean Tregs/CD4 cells for treated subjects was 2.89% (range 1.06-5.40) at baseline and 3.11% (range .81-5.13) at day 14. For 6 patients who received ≥2 cycles, mean Tregs/CD4 cells dropped to 1.95% (range .71-3.74) at day 42 and 1.65% (range .78-2.36) at day 70. CD8+CD28- Tregs were only increased (>50% of CD8 T-cells) in 2 patients and not correlated with remission duration. Conclusions: These data suggest that denileukin diftitox depletes Tregs in relapsed ovarian cancer only with repeated dosing and may be of clinical value in MRD.
Effect of cryopreservation, type of antigen, and route of administration on in vivo migration of human monocyte-derived dendritic cells.
Authors: Nicol Andrew John , Tazbirkova Andrea , Macfarlane David , Nieda Mie
Published: March 2020

e13128

Background: Immunotherapy strategies using antigen loaded dendritic cells are being widely utilized in clinical trials for patients with malignancies. To induce effective immune responses against tumors, dendritic cells need to traffic into areas rich in immune effector cells such as T cells and natural killer T cells. In our study, we investigated localization of monocyte derived dendritic cells (MoDC) following different routes of administration, and whether cryopreservation or type of antigen has an impact on MoDC trafficking properties. Methods: Twelve patients with metastatic malignancies received 111Indium-oxine labeled MoDC pulsed with peptide/protein based antigen or glycolipid antigen, which was administered intradermally, subcutaneously or intravenously, and fresh or after a cryopreservation step. Results: Following intravenous administration, MoDC rapidly distributed into lungs, followed by liver and spleen. In nine of twelve cases intradermally administered MoDC migrated to regional lymph nodes but this was true only for one of nine MoDC injections administered subcutaneously. Cryopreservation and type of antigen did not influence migration capabilities of MoDC. Conclusions: Our data confirms that MoDC trafficking is markedly dependent on the mode of delivery. There is no difference in trafficking of MoDC administered fresh or after cryopreservation and the type of antigen does not have impact on MoDC distribution in the human body.
Association between elevated blood pressure and clinical response in patients treated with anti-vascular endothelial growth factor (anti-VEGF) therapy in phase I clinical trials.
Authors: Bilen Mehmet Asim , Naing Aung , Hong David S. , Falchook Gerald Steven , Fu Siqing , Wen Sijin , Wheler Jennifer J. , Durand Jean-Bernard , Ewer Michael , Kurzrock Razelle
Published: March 2020

e13506

Background: Relationship between elevated blood pressure and clinical response in patients with advanced cancers treated with anti-VEGF treatment was evaluated. Methods: We performed an analysis of 438 consecutive patients from 19 clinical trials treated with therapy that included an anti-VEGF agent starting January, 2006. Clinical response was determined by RECIST 1.0. Blood pressures (BP) were scored as shown in Table. BP scores were calculated from an average mean BP of all BP readings for each patient, taken at each visit, and then divided into time points: baseline, 4, 8 and 12 months. Other factor included number of medication. Scores at each time point were compared to baseline value and divided into: increasing, decreasing and stable. Chi-square was used to correlate increased BP scores with clinical response. Additional analysis was also done by using CTCAE v4.02 for grading of BP. Results: The median age was 57 years (13 to 88) and 54% were male; 10% of patients received more than one anti-VEGF therapy. The median number of anti-VEGF therapies was 2 (1 to 3). Within the first four months, 52% of patients who achieved partial response (PR) had increased BP scores from baseline compared to 18% of those with progressive disease (PD) and 25% of those with stable disease (SD) (p <0.0001) (CTCAE; p=0.004) but there was no difference between SD and PD (p = 0.11) (CTCAE; p=0.31). The elevation in BP scores was significantly higher in the PR+SD group (31%) compared to PD group (18%) within 4 months (p=0.008) (CTCAE; p=0.07). There is a significant difference in increased BP scores among PR to SD groups within 8 months and 12 months (p=0.04 and p=0.028) (CTCAE; p=0.04 and p=0.107). Conclusions: Increasing BP scores is a positive prognostic indicator for favorable clinical response in patients who received anti-VEGF treatment. [Table: see text]
Use of PTEN status to determine the functional outcome of combined MEK and mTOR inhibition.
Authors: Ciuffreda Ludovica , Falcone Italia , Cesta Incani Ursula , Sette Giovanni , Eramo Adriana , Del Curatolo Anais , De Maria Ruggero , Cognetti Francesco , Milella Michele
Published: March 2020

e13512

Background: PTEN is a lipid phosphatase couteracting the activity of the PI3K pathway. PTEN mutations and deficiencies are prevalent in many types of human cancers and are associated with poor prognosis and therapeutic resistance. MAPK is another key cellular network that works independently from, in parallel to, and/or through interconnections with PI3K to promote cancer development. Here we investigated whether a strategy combining MEK and mTOR inhibition may be effective in preclinical models of human cancer and the role of PTEN loss in determining sensivity/resistance to single and combined pathway inhibition. Methods: We employed in vitro assays (cell proliferation assays, cell cycle and apoptosis analysis, WB, and ELISA assays) to determine functional and molecular drug effects. Pharmacologic interactions between MEK and mTOR inhibitors were analyzed by conservative isobologram analysis using a fixed dose-ratio experimental design. Results: In cell lines with wt-PTEN (including melanoma, breast, lung, and colon cancer), combined MEK and mTOR blockade achieves synergistic effects at suboptimal drug concentrations but becomes frankly antagonistic in the presence of complete inhibition of MEK-to-ERK signaling (combination index - CI: 1.2->1000). This, in turn, led to the identification of a novel crosstalk mechanism by which MEK blockade restores PTEN expression and cross-inhibits the PI3K/AKT/mTOR pathway, thus bypassing the need for double pathway blockade. Conversely, in cancer cell lines with PTEN loss, combined MEK and mTOR blockade resulted in strongly synergistic effects (CI: 0.0005-0.4), due to cooperative induction of apoptosis. A similar synergistic growth inhibition was also observed in a patient-derived lung cancer stem cell line, which displayed low to undetectable PTEN protein levels. Conclusions: Our results suggest that combined MEK and mTOR inhibition exerts strongly synergistic effects in cancer models with PTEN loss. This notion may be helpful in selecting appropriate cellular (and possibly clinical) contexts for the design rational therapeutic strategies based on concomitant inhibition of the RAF/MEK/ERK and PI3K/AKT/mTOR pathways.
Sorafenib in the treatment of metastatic paraganglioma: A case report.
Authors: Gunaldi Meral , Kara Ismail Oguz , Usul Afsar Cigdem , Duman Berna Bozkurt
Published: March 2020

e13523

Background: Paragangliomas (extra-adrenal pheochromocytomas) are rare chromaffin cell tumors that can often be cured by resection. Excess release of catecholamines is characteristic for paragangliomas. Paragangliomas are mostly benign if diagnosed and treated early. Overall 0–36% of paraganglioma patients develop metastatic disease, depending on the type of tumor. Methods: We present a case of a 43-year-old woman who admitted to our department with a history of episodic headaches, diaphoresis and weakness. Hypertension and tachycardia were diagnosed. She had elevated plasma catecholamine levels and a right paraaortic mass (9x9.5cm) was visualized on CT. The mass was excised and the diagnosis of paraganglioma was confirmed. In postoperative follow-up the patient's blood pressure and catecholamine levels were normalized. After twenty months follow up, local recurrence and metastases were detected in thorax, abdomen, and skeletal system. Plasma catecholamine levels were high. Results: Chemotherapy with CVD (adriamycine (7mg/m2), dacarbazine (400mg/m2), cyclophosphamide (500mg/m2), vincristine (1.4mg/m2) on day 1 and 2, repeated every 21 days; were administered and no improvement was observed in PET-CT following a treatment of three cycles. Sorafenib (800mg/m2/day) was applied for three-months. Finally the patient’s plasma catecholamine levels and metastatic lesions regressed. Conclusions: Treatment options of metastatic paragangliomas (MP) are removal by excision or ablation, chemotherapy, or targeted pharmaceuticals. Benefits of CVD chemotherapy for MP appears to be short-term and do not include an increase in patient survival. As targeted therapy, treatment of MP with everolimus or imatinib were attempted with no significant benefit, and thus are not recommended. However partial response was reported with Sunitinib some cases. We used sorafenib as another multiple TKI and detected complete response. So far, sorafenib has not been applied in the treatment of MP in literature. Sorafenib can be preferred in the treatment of MP. Therefore, more comprehensive clinical trials are needed.
Transcriptional inhibition of Notch signaling using cell penetrating fusion proteins.
Authors: Epenetos Agamemnon A. , Colucci Silvia , Deonarain Mahendra , Stylianou Spyros
Published: March 2020

e13525

Background: Notch signalling is deregulated in a number of cancers and is possibly involved in cancer stem cell development. It is postulated that cancers such as breast can become addicted to Notch signalling presenting opportunities for tumour-specific intervention. Due to the presence of at least 4 cell surface receptors that mediate Notch signalling, conventional targeting agents such as monoclonal antibodies cannot inhibit them all. As all the signalling cascades converge on the Notch transcriptional complex (NTC) in the nucleus, inhibition of gene expression by disrupting this machinery is an attractive strategy to overcome this redundancy. Methods: Towards this, we have developed a fusion protein based on the potent cell penetrating protein (CPP) antennapedia (Antp) recombinantly fused to a dominant-negative truncated mastermind-like protein (DN-MAML) called TR4. We have also developed a method of incorporating CPP to deliver intracellular antibody fragments against nuclear targets such as Notch and mastermind. Results: The Antp-DN-MAML protein (TR4) has similar potency to many of the gamma-secretase inhibitors being developed against this pathway but more specific for the NTC.TR4 can inhibit tumour cells in vitro and in vivo and provide some insight into the mechanism of action. Also such intracellular targets are accessible to antibodies, provided they are delivered using CPP such as antennapedia. Conclusions: .As a model system, scFvs have been raised to key epitopes in the NTC which can lead to complex inhibition and the same downstream effects as TR4.In addition, we further demonstrate that there is a more general approach to trascription factor inhibition using single-chain Fvs fused to Antp
Antitumor effect of Chinese herb oridonin on human non-small cell lung cancer (NSCLC).
Authors: Chen Siyu , Tian Wei , Ma Ai-Hong , Desai Sonal , Tolentino Krysteena , Guo Yantong , Li Tianhong
Published: March 2020

e13526

Background: Oridonin, a diterpenoid purified from the Chinese herb Rabdosia rubescens, has anti-inflammatory and potentially anti-tumor property. We aimed to study the antitumor effect of oridonin on a panel of human non-small cell lung cancer (NSCLC) cell lines. Methods: Human NSCLC cell lines with a wild-type EGFR gene and a RAS gene mutation were treated with escalating dose concentration of oridonin (from 2.5 to 50 µM). Antitumor effect was measured by 72-hr growth inhibition by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell morphology was observed under microscope. Ongoing experiments will identify potential drug target(s) by assessing changes in global gene expression. Results: Oridonin exhibited a dose-dependent and time-dependent cytotoxic effect on a panel of NSCLC cell lines. Table 1 summarizes the molecular and histological features of these NSCLC cells, and their cytotoxicity to oridinin, erlotinib and pemetrexed. In those NSCLC cells that were sensitive to oridonin, morphological changes were consistent with autophagy and apoptosis. Potential drug targets will be verified by RT-PCR and immunoblotting. Conclusions: Oridonin exerts a distinct cytotoxicity that is independent of the sensitivity of NSCLC cells to erlotinib or pemetrexed. Further mechanistic and animal studies are warranted to understand its anti-tumor property and toxicity profile in preclinical evaluation. [Table: see text]
A pipeline to detect antibody-targetable cancer stem cell proteins.
Authors: Calogero Raffaele A , Lanzardo Stefania , Conti Laura , Cavallo Federica
Published: March 2020

e13527

Background: Monoclonal antibody represents an ideal tool to develop highly specific drugs. However, the efficacy of antibody-based drugs is strongly dependent by the effect that the protein targeted will have on the disease cell. Particularly interesting, as target for antibody therapy, are oncoantigens (OAs), i.e., surface tumor antigen that supports tumor growth. Methods: We have developed a two steps pipeline that allows identifying moAbs directed against e.g., cancer stem cells (CSC) OAs. First step: we compare transcription profiles, derived by tumor cell line grown as epithelial monolayer, with those derived by spheroids generated using the same cell line. Since spheroids are enriched in CSCs, genes up-modulated in spheroids are putative targets for antibody-targeting. Putative targets are ranked on the basis of their oncological potential and low expression in normal tissues. Top ranking targets are then tested in animal model. If vaccination inducing antibody response is able to reduce tumour growth and/or metastasis formation targets are proficient for the second step: they are used to vaccinate BALB/c mice. IgG expressing cells are isolated and libraries of the heavy (HV) and light variable (LV) chains are sequenced. Bioinformatics is then used to detect enriched VH and VL, which are transformed in single-chain antibodies to test target binding efficacy. Results: Using our pipeline we have identified, as associated to HER2+ breast cancer cell, TMPRSS4. This protein is involved in metastasis and invasion and, in hepatocellular carcinoma, it is over-expression leads to epithelial-mesenchymal transition. We are now evaluating if antibodies raised against TMPRSS4 are able to inhibit metastasis formation in BALB/c mice. On the basis of these results we will move to the second step of the pipeline. Conclusions: We have designed a pipeline that allows identification of CSC associated proteins suitable as targets for antibody-driven therapy.
Docetaxel followed by temsirolimus in suppression of mTOR pathway.
Authors: Huang Chao H , Van Veldhuizen Peter J. , Gadashova Ayten , Williamson Stephen K. , Farassati Faris
Published: March 2020

e13535

Background: Mammalian target of rapamicin(mTOR) is a downstream regulatory protein of the PI3K/Akt signal transduction pathway. This is a common pathway for a several cell surface receptors including IGFR (Insulin-like Growth Factor Receptor) and EGFR (Epidermal Growth Factor Receptor). The activation of these receptors through PI3K/Akt pathway is essential in cell proliferation, angiogenesis and anti-apoptosis process. Several therapeutic agents that inhibit these receptors have shown to be active in the treatment of diverse types of cancers. Docetaxel (D) is commonly used in the treatment of lung cancer. We demonstrated previously that the sequence of D followed by mTOR inhibition using temsirolimus (T) in lung cancer cell lines (LCCL) had synergistic effect in suppressing cell proliferation compared with T→D. The exact mechanism of this effect is unknown. We studied the expression of mTOR, Raptor and PI3K in these cell lines treated in different time points to investigate the activity of this pathway when using these sequences of drug treatment. Methods: Adenocarcinoma LCCL H2122 and H1437 were plated and exposed to temsirolimus 1000nM and docetaxel 100nM. The cell viability was measured by optical density (OD) at 24, 48 and 72h. We tested the sequence of D treated for 24h followed by addition of T and the reverse in both LCCL. We then prepared cell lysate at 24h, 48h and 72h time points and studied the expression of mTOR, Raptor and PI3K by western blot using antibody obtained from Cell Signaling. Results: The sequence of D→T had increased suppression of mTOR, Raptor and PI3K at 48 and 72 hours compared with the opposite sequence of T→D. Conclusions: The combination of D → T seems to have synergistic suppression of mTOR and PI3K pathway in 2 LCCL compared with opposite sequence. Further studies in animal models using this sequence and confirmation of mTOR suppression may help determine if this is a feasible combination in the treatment of lung cancer.
Reliability of imaging biomarkers for response assessment in advanced lung cancer: Influence of expertise and automation.
Authors: Beaumont Hubert , Oubel Estanislao , Iannessi Antoine , Wormanns Dag
Published: March 2020

e13547

Background: Image-based biomarkers play an important role in the assessment of the response to therapy. The value of imaging biomarkers relies on their reproducibility, which depends on the reviewer and on the measuring system. This study aims at evaluating the impact of readers’ expertise and automation of measurements. Methods: A retrospective study was performed on 10 patients with at least one Non-Small Cell Lung Cancer (NSCLC) lesion, and followed over time (7 time points in average) with Computed Tomography (CT). 2 expert radiologists (ERs) and 5 imaging scientists (ISs) measured the Longest Axial Diameter (LAD) and the volume (VOL) of each lesion at each time point. ERs and ISs segmented the lesions by using a proprietary software providing semi-automatic segmentation processing with manual adjustment. ISs performed an additional session using manual segmentation tools only. From each segmentation, VOL and LAD were automatically computed. The variability of the measurements was calculated by using standard statistics. The response to treatment was assessed according to RECIST thresholds for LAD and with +/-30% thresholds for volume. The inter-reader agreement was measured trough the Kappa coefficient. Finally, the reviewing time with and without automation was analyzed. Results: The use of automated tools by ISs reduced the standard deviation of LAD difference from 10.7% to 8.4%. The inter-reader agreement improved Kappa from 0.57 to 0.68 for LAD, and from 0.52 to 0.69 for VOL. The automation reduced the reviewing time by a factor 4 with respect to the manual assessment. No significant differences in variability were found between ISs and the first ER, but significant differences were observed with respect to the second ER. Conclusions: In a RECIST context, automation improved significantly inter-reader agreement. When using volume as a biomarker, automation not only improved the inter-reader agreement, but also decreased notably the reviewing time. No evidence was found about the influence of the expertise on the volume measurement. The difference in the lesions interpretation by the experts is a relevant factor to account for.
Isolated chemotherapeutic perfusion as neoadjuvant therapy for advanced/unresectable plevic malignancy.
Authors: Wanebo Harold J. , DiSiena Michael Ross , Belliveau James , Gustafson Eric
Published: March 2020

e13561

Background: Isolated pelvic perfusion (IPP) may have value in therapy of recurrent pelvic malignancy following previous surgery and chemoradiation. We performed 113 IPP in 78 such pts (34 palliation, and 44 pre op) using a simplified balloon occlusion technique. Methods: Of 42 patients (pts) with recurrent rectal cancer (ca), 26 had preop and 16 had palliative IPP. Other pelvic cancers included anal canal (8 pts), pelvic sarcoma (5 pts), melanoma (M) (4 pts), endometrial ca (EC) 2 pts, ovarian ca (OC) 2 pts, and bladder ca (BC) 1 pt. Chemo agents included Paclitaxel, 5FU, cisplatinum, or Oxaliplatin and mitomycin for epithelial cancer and (Doxorubicin, Ifosamide, Phenyl Alanine Mustard (PAM) for remaining tumors. High dose IPP with PAM, Paclitaxel and Cisplatin was given in 6 pts, 3 with stem cell support. Results: Palliative IPP in advanced rectal cancer (AdRca) pts relieved narcotic resistant pain (2-4 mos) in 11/16 pts (69%). Preop IPP in 26 AdRca achieved path CR in 2 pts and partial regression in 11 pts; 7 had RO resection. Of 5 other pts, 3 refused resection, 2 were inoperable. Median survival was 17 mos in 12 resectable pts and 30 mos in 7 resected pts and 8 mos in 12 non resectable pts. It was 30 months in 8 pts with anorectal ca (1>90 mos), 20 mos in 4 endometrial/ovarian ca pts, (1 died NED >48 mos), 13 mos in 4 M pts and 5 (4-34) mos in 5 pelvic sarcoma pts. Overall 17 of 44 (39%) were resected and 24 were palliated with IPP. Conclusions: IPP has value in palliating or augmenting resectability and survival in advanced pelvic cancer patients not amenable to conventional chemoradiation and surgery.
Evaluation of KPT-SINE (Selective Inhibitors of CRM1-Mediated Nuclear Export) in AML and T-ALL.
Authors: Etchin Julia , Kentsis Alex , Sanda Takaomi , Kung Andrew L. , Stone Richard M. , McCauley Dilara , Kauffman Michael , Shacham Sharon , Look A. Thomas
Published: March 2020

e13586

Background: CRM1 is the major nuclear exporter that mediates transport of a variety of molecules, including proteins involved in tumor suppressor and cellular proliferation pathways. The crystal structure of CRM1, in complex with its export cargo, Snurportin 1, has been recently resolved. The molecular understanding of the CRM1-cargo binding interface has led to the development of novel small molecule inhibitors of CRM1-cargo interaction, termed KPT-Selective Inhibitors of Nuclear Export (SINE). KPT-SINE are potent, drug-like CRM1 inhibitors that irreversibly inactivate the CRM1-directed protein export by covalent modification of the essential CRM1-cargo binding residue Cys528. The inhibition of the CRM1 nuclear export has been shown to lead to selective apoptosis in cancer cells when compared to normal cells. Here, we assess the efficacy of the KPT-SINE in human AML, T-ALL, and normal hematopoietic cells. Methods: The viability of a panel of human AML and T-ALL cell lines upon treatment by the KPT-SINE was assessed. Dose-response measurements were done using serial dilutions of KPT-SINE from 1 µM to 0.3 nM and luminescent cell viability assay. Apoptosis was measured using Annexin V staining and TUNEL assays. Results: KPT-SINE induces rapid apoptosis in 10 of 14 AML and 12 of 15 T-ALL cell lines with IC50s of 15-100 nM. In the KPT-SINE-sensitive cell lines, BCL2 overexpression suppresses KPT-SINE-induced apoptosis, indicating its intrinsic pathway mediation. Importantly, KPT-SINE compounds, either KPT-251 at 75 mg/kg or KPT-330 at 15 or 25 mg/kg, induced remarkable growth suppression in MV4-11 human AML cells engrafted into immunodeficient NSG mice with minimal toxicity to normal mouse hematopoietic cells after 35 days of treatment. Bone marrow biopsies of KPT-treated mice were remarkable in that they showed normal hematopoietic cell morphology and cellularity after 35 days of treatment. Xenograft studies to address the potency of the KPT-251 and KPT-330 on MOLT-4 human T-ALL cells in vivo are ongoing. Conclusions: These studies emphasize the clinical promise of the KPT-SINE as a novel and selective drug candidate for the treatment of AML and T-ALL.
Pharmacodynamic evaluation of pCDC2 as the target engagement biomarker to assess activity of MK-1775 a Wee1 tyrosine kinase inhibitor.
Authors: Rose Shelonitda , Cheng Jonathan D. , Viscusi Johnny , Iannone Robert , Schellens Jan HM , Leijen Suzanne , Shapiro Geoffrey , Pavlick Anna C. , Oza Amit M. , Rosen Lee S. , Tosolini Alessandra , Lam Raymond , Demuth Tim
Published: March 2020

e13598

Background: Wee1 kinase regulates the G2 checkpoint through phosphorylation of CDC2. MK-1775 is a first-in-class inhibitor of Wee1, and thereby reduces pCDC2 levels relative to CDC2. pCDC2therefore can be used as a target engagement (TE) biomarker to assess activity of MK-1775. This was investigated in a phase I first-in-man clinical trial of MK-1775. Methods: This is a multicenter, open-label, non-randomized phase I dose escalation study in patients with locally advanced or metastatic solid tumors. MK-1775 was administered orally in escalating doses as monotherapy, and either single dose or multi-dose in combination with chemotherapy including cisplatin, carboplatin and gemcitabine. Serial skin biopsies were performed at baseline and either 8, 24 or 48 hours following MK-1775 administration and analyzed by IHC for CDC2 and pCDC2. Based on preclinical efficacy experiments, TE was defined as a decrease of pCDC2 of at least 50% (or fold change > 0.50) from pre- to post-dose MK-1775. Results: To date a total of 176 patients have received at least one dose of MK-1775 either as monotherapy or in combination (single or multi-dose MK-1775) with chemotherapy at doses ranging from 25 mg to 1300 mg to define maximum tolerated dose. Dose dependent decreases in pCDC2 were observed in skin biopsies between pre-dose and post-dose treatment in all treatment groups. TE with monotherapy was achieved at 325 mg. TE with multi-dose MK-1775 in combination with cisplatin and carboplatin were achieved at 125 mg BID and 225 mg BID. Gemcitabinecombination treatment is on-going. In contrast, chemotherapy alone resulted in an increase of pCDC2. Conclusions: Based on preclinical data, in this first-in-man clinical trial of MK-1775, we were able to demonstrate TE required for maximal efficacy at tolerable doses of MK-1775 either as a single agent or in combination with chemotherapy. [Table: see text]
A phase I dose escalation study of oral MK-2206 (allosteric Akt inhibitor) with oral selumetinib (AZD6244; ARRY-142866) (MEK 1/2 inhibitor) in patients with advanced or metastatic solid tumors.
Authors: Khan Khurum Hayat , Yan Li , Mezynski Janusz , Patnaik Amita , Moreno Victor , Papadopoulos Kyriakos P. , Garrett Chris R. , Ong Michael , Shannon Keith A. , Morosky Anne , Rubin Eric H. , Tetteh Ernestina , Skolnik Jeffrey , Smith Ian C. , Smith Paul D. , De Bono Johann Sebastian , Tolcher Anthony W.
Published: March 2020

e13599

Background: Simultaneous inhibition of both the PI3K-Akt and RAF/MEK/ERK pathways may yield greater benefits than inhibiting either pathway alone. This phase I study (NCT01021748) examined the safety, pharmacokinetics (PK), pharmacodynamics (PD), maximal tolerated dose (MTD), and preliminary antitumor activity of the combination of a MEKi (selumetinib) and AKTi (MK-2206). Methods: Eligible patients (pts) with advanced solid tumors were treated with MK-2206 either every other day (QOD) or once weekly (QW), in combination with selumetinib administered either once daily (QD) or twice daily (BID). Results: 51 pts with advanced solid tumors (15 colon, 8 NSCLC, 6 ovarian, 5 pancreatic, 3 breast and 14 others) were treated across 9 dose levels. There were 2 confirmed partial response (PR) (1 NSCLC, ongoing > 52 wks; 1 ovarian, on treatment for 47 weeks; both KRAS mutation positive), 1 unconfirmed PR (pancreatic, on treatment 20 wks), and 24 pts with stable disease (ranged from 6 to 47 wks). Preliminary assessment of PK data suggested no apparent drug-drug interactions with unaltered PK profiles of each drug when administered in combination. Conclusions: In combination the maximum tolerated doses of MK-2206 and selumetinib are 135 mg QW and 100 mg QD, respectively. This combination of investigational agents demonstrated preliminary antitumor activity in pts with advanced cancer. [Table: see text]
A phase I study of MDM2 antagonist RG7112 in patients (pts) with relapsed/refractory solid tumors.
Authors: Kurzrock Razelle , Blay Jean-Yves , Bui Nguyen Binh , Wagner Andrew J. , Maki Robert G. , Schwartz Gary K. , Patnaik Amita , Gore Lia , Wu Lin , Vassilev Lyubomir T , Ding Michelle , Geho David , Zhi Jianguo , Middleton Steven , Nichols Gwen L.
Published: March 2020

e13600^

Background: RG7112 is a small molecule MDM2 antagonist, designed to non-genotoxically activate p53. A phase I dose escalation (DE) was performed, followed by a sarcoma biomarker extension (EXT) in pts with wild type TP53. Methods: 106 pts (58M, 48 F), median age 57.9 yrs (range 22-84) participated; 76 in 9 cohorts (DE) from 20 to 1800 mg/m2, orally QD x 10 q28 days. 30 pts with sarcoma were treated at MTD (2500 mg) (EXT) with pre-and on dose (d5+/-2) biopsies. Analyses included TP53 mutation (AmpliChip), MDM2 amplification (ISH), p53 and p21 IHC, MDM2 RT-PCR, Ki-67, TUNEL and [18F]-FLT-PET. Blood was obtained for PK and MIC-1, a PD marker of p53 activation. Results: DE: MTD was1440 mg/m2/d (2500 mg flat dose). PK was ~dose linear (t½ 1-1.5 d) with high variability (CV~70%) in AUC and Cmax . Adverse events included nausea/GI and exposure-related neutropenia/thrombocytopenia. 3 DLTs: diarrhea, pancytopenia, hyponatremia occurred (at ≥ 640 mg/m2). Evidence of activity included: 1) concentration dependent increase in plasma MIC-1 (% baseline), 2) decrease in [18F]-FLT PET and PR each in liposarcoma pts at 1800 mg/m2 and 1440 mg/m2, respectively. EXT: Grade3/ 4 cytopenias at MTD precluded subsequent cycles in 6/8 pts (10 day schedule). Dosing was changed to 5 days, and only 3 patients had Gr3/4 cytopenias. 8/22 pts remained on study for >4 cycles, including 2 pts with SD for 7 and 9 cycles respectively. 3 of 4 EXT pts had decreased [18F]-FLT-PET activity. Biopsies (pre- and on treatment) demonstrated: 1) increase in p53 (median 1.5 fold change (X) by IHC, n=15); 2) increase in p21 (median 2.7X by IHC, n=14); 3) increase in MDM2 (median 2.5X by RT-PCR, n = 27); 4) decrease in % Ki-67(+) cells (median % change from baseline -65.4%, range -91% to +275%, n=17 ); 5) increase in TUNEL(+) cells of 9.0 (density of + cells/mm2, range -26.2 to +45.5, n=22). These results were seen both in tumors with and without MDM2 gene amplification, and in multiple sarcoma subtypes. Conclusions: RG7112 has manageable AEs (GI ) and cytopenias correlating with AUC. Single agent disease control, and biomarker activity was seen in both MDM2 amplified and non-amplified, heavily pretreated soft tissue sarcoma pts, with changes reflecting activation of p53-related pathways.
Relationship of loss of miRNA-296 in the circulation and clinical outcome in patients receiving systemic chemotherapy for metastatic colon cancer.
Authors: Mikhail Sameh , Shivapurkar Narayan , Bai Wei , Marshall John , Hwang Jimmy J. , Pishvaian Michael J. , Wellstein Anton , He Aiwu Ruth
Published: March 2020

e14009

Background: Several studies highlighted the potential for serum microRNA (miRNA) as prognostic and/or predictive markers. We describe an association between miR-296 and outcomes in a phase II trial of sunitinib and capecitabine in first line treatment of patients with metastatic colorectal cancer. Methods: Serum samples were obtained from subjects at (1) Screening (2) Prior to start of study drug (3) Every four weeks while on study. We compared miRNA levels and response to treatment at baseline and at four weeks. Results: Serum from seven patients was used to run miRNA array (382 miRNAs). Among the seven patients, three patients had decrease in the level of miR-296 at 4 weeks (Table). These patients were on the study treatment for a mean duration of 2.5 months (median 1.9). They had a mean survival from the time of diagnosis of 10.5 months (median 10.4) and a mean survival from time of enrollment of 7.5 months (median 8.7). Four patients had increase in the level of miR-296 at 4 weeks. These four patients were on the study treatment for a mean duration of 5 months (median 5). They had a mean survival from the time of diagnosis of 22.8 months (median 22) and a mean survival from study entry of 17.1 months (median 18.3). The duration on study treatment and the difference in survival from diagnosis, between the two groups were statistically significant (p=0 .014 and p=0.0025, respectively). Patients with shorter survival and poor clinical outcome had decrease in the level of miR-296 at four weeks from the start of treatment (0.43 versus 28 for patients with better clinical outcome; p=0.035). Conclusions: In our study, miR-296, served as a predictive and prognostic marker for clinical outcome of patients receiving systemic treatment for advanced colorectal cancer. Further studies are needed to confirm our results in a larger population. [Table: see text]
A phase II multicenter trial of mFOLFOX6 as adjuvant treatment after resection of liver metastases from colorectal cancer (Miyagi-HBPCOG Trial-001): The final data of progression-free survival.
Authors: Katayose Yu , Yamamoto Kuniharu , Takemura Shinichi , Takahashi Michinaga , Nakamura Ryuji , Shimamura Hiromune , Asanuma Taku , Uchiyama Tetsuyuki , Endo Kojin , Oikawa Masaya , Shiiba Kenichi , Nakagawa Kei , Egawa Shinichi , Unno Michiaki ,   Miyagi-HBPCOG
Published: March 2020

e14011

Background: Perioperative chemotherapy with FOLFOX4 reduces the progression-free survival of patients with liver metastases from colorectal cancer. However, the benefit of adjuvant treatment after hepatectomy has not been clarified yet. Here, we evaluated the efficacy of treatment with mFOLFOX6 in a postoperative adjuvant setting. Methods: We recruited 49 patients from 17 hospitals (Japan) between July 2006 and June 2009 who were histologically proved to have colorectal cancer. The primary tumor had to be resected with R0 or R1 resection, and no detectable extrahepatic metastases. This report is the trial’s final data for progression-free survival (PFS) in all enrolled cases, while overall survival is still being monitored. The regimen was 12 cycle of mFOLFOX6. The primary endpoint was progression-free survival. This study was planned to detect a 20% increase in median PFS from 40% to 60% in all assigned patients based on the data of several previous surgeries, and the set of 50 cases. Results: 1 patient did not start the protocol treatment because liver metastases were detected before starting. 48 patients started the protocol treatment. 4 patients committed a protocol violation. Excluding this 4 violation cases from the 49 cases, 33 cases (75%) received 10 course (83.3%) of mFOLFOX6. The dose intensities of oxaliplatin, leucovorin, and 5-FU were 75.9%, 80.5%, 78%, respectively in all enrolled cases. The PFS at 2 years was 59.2%. The median survival time was 49 months. The PFS for single liver metastasis was better than that for multiple metastases (Wilcoxon test: p<0.05). Overall survival was 72%. There were no Grade 4 adverse events (AE) or deaths related to chemotherapy. In Grade 3 AE, neutropenia, sensory disturbance, thrombocytopenia, and allergy were 37.5%, 8.3%, 8.3%, and 8.3%, respectively. Conclusions: Adjuvant treatment with mFOLFOX6 is feasible and could greatly improve the PFS without biologics. The benefit of this therapy with mFOLFOX6 as an adjuvant treatment needs to be evaluated further as compared to perioperative chemotherapy.
Identification of the biomarkers for the prediction of efficacy in the first-line chemotherapy of metastatic colorectal cancer patients using SELDI-TOF-MS and artificial neural networks.
Authors: Yuan Ying , Shen Hong , Li Mo-Dan , Tan Chun-Wen , Yu Jie-Kai , Fang Xue-Feng , Zheng Shu
Published: March 2020

e14026

Background: For patients with metastatic colorectal cancer, both FOLFOX regimen and FOLFIRI regimen are considered as first-line choices. However, only about half of patients could have an obvious response, and there are no clinically useful markers that could predict the response to these regimens respectively. A major clinical challenge is to identify the subset of patients who could benefit from those regimens. We aimed at identifying serum protein patterns which could predict the efficacy of chemotherapy. Methods: Serum from 70 patients diagnosed as metastatic colorectal cancer before first-line chemotherapy were collected and analyzed for protein patterns using artificial neural networks (ANN) analysis of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Among the 70 cases, 44 patients received FOLFOX chemotherapy, while the other 26 patients received FOLFIRI chemotherapy. After four cycles of the treatment, RECIST criteria were used to define the responders (R) and non-responders (NR). Results: With the method of SELDI-TOF-MS,a potential predicting pattern consisting of 6 biomarkers (9,298m/z, 9,282m/z, 4,606m/z, 9,198m/z, 7,775m/z and 2,266m/z) was identified in the patients receiving FOLFOX chemotherapy. Using this predicting pattern, the responders could be separated from the non-responders with a sensitivity of 92.9%, and a specificity of 81.3%. Another potential predicting pattern that consisted of 7 biomarkers (4,321m/z, 4,305m/z, 2,648m/z, 2,952m/z, 4,121m/z, 4,292m/z and 3,980 m/z) was identified in the patients who have received FOLFIRI chemotherapy. Using this predicting pattern, the responders could be separated from the non-responders with a sensitivity of 92.3% and a specificity of 92.3 %. Conclusions: Two potential patterns for the prediction of efficacy of FOLFOX or FOLFIRI chemotherapy were established in this preliminary study. These protein patterns could be helpful for oncologists to make a decision in selecting suitable first-line regimens for metastatic colorectal cancer patients.
Frequency of second- and third-line treatment among elderly Medicare stage IV colon cancer patients.
Authors: Mullins C. Daniel , Bikov Kaloyan A , Onukwugha Ebere , Seal Brian S. , Hanna Nader
Published: March 2020

e14035

Background: Stage IV colon cancer (CC4) patients may receive multiple lines of chemotherapy and/or biologics as treatment (TX) to improve survival or quality of life, yet elderly patients generally receive less aggressive cancer TX. Methods: Elderly (65+) SEER-Medicare patients diagnosed with CC4 in 2003-7 were followed through death or 2009 to examine variation across sub-groups in the number of TX lines. TX included 5-fluorouracil and (levo)leucovorin-based (5FU/LV); irinotecan (IRI) and/or oxaliplatin (OX) with/out 5FU/LV; bevacizumab, cetuximab, or panitumumab (MNCLA), alone or in combination with chemotherapy; and other TX. A hierarchy categorized treatments as: 1) IROX (IRI+OX); 2) IRI or OX; 3) 5FU/LV; 4) MNCLA without chemotherapy; and 5) other TX. Gaps in TX or changes from OX or IRI to 5FU/LV were not considered new lines. Results: Of 7,937 elderly CC4 patients, 3,263 (41%) received any TX, while 1,541 (19%) and 570 (7%) received second and third line TX, respectively. Among the TX group, younger (p<0.01), married (51 vs. 42%, p < 0.01) and male (49 vs. 45%, p = 0.02) patients were more likely to go on to second line TX. Medicare buy-in coverage, which generally indicates dual Medicaid-Medicare coverage (42 vs. 48%, p = 0.03), lowered the likelihood of second line TX. Having comorbidities impacted initial TX (CCI=0: 44.5%, CCI=1: 41.9%, CCI=2: 28.4% ; p<0.01) more so than the likelihood of second (CCI=0: 48.6%, CCI=1: 45.9%, CCI=2: 42.4% ; p=0.06) or third (CCI=0: 37.2%, CCI=1: 39.9%, CCI=2: 29.9% ; p=0.09) line TX conditional upon receipt of prior line treatment. There was no significant association between second line TX and race/ethnicity, urbanicity or year of cancer diagnosis. Among those with second line TX, only age (p=0.05) and urbanicity (38 urban vs. 25% non urban, p < 0.01) were significantly associated with higher likelihood of third line TX. Conclusions: Among CC4 patients with TX, married patients and men receive more TX lines, while number of treatment lines decreases with age. Tendency to use less aggressive treatment with elderly CC4 patients, combined with our observed results, suggests that a substantial proportion of elderly CC4 patients receive fewer TX lines than equivalent younger patients.
Effect of brain-derived neurotrophic factor/TrkB axis on cancer progression in colorectal cancer.
Authors: Inoue Yasuhiro , Okugawa Yoshinaga , Saigusa Susumu , Hiro Junichiro , Toiyama Yuji , Tanaka Koji , Mohri Yasuhiko , Kusunoki Masato
Published: March 2020

e14039

Background: Brain-derived neurotrophic factor (BDNF) is one of the member of the neurotropin family known to activate the high affinity tyrosine kinase B (TrkB) receptor together with the pan-neurotropin low-affinity coreceptor p75 (p75NTR). TrkB activation by BDNF has been shown to facilitate the progression of several cancers, however, no reports have shown the clinical and biological effects of BDNF/TrkB axis expression in colorectal cancer(CRC). Methods: A total of 223 consecutive patients undergoing surgery for CRC were enrolled. We analyzed BDNF/TrkB mRNA levels by real-time reverse transcription PCR in CRC tissues, and their relationships with clinicopathological findings including survival were investigated. BDNF and TrkB expression were also evaluated by immunohistochemistry. To investigate the biological role of the BDNF/TrkB axis, recombinant human BDNF and Trk antagonist K252a were used for proliferation, migration, and anoikis assays in CRC cell lines. Results: The mean BDNF level in CRC tissue was 94.3 (0-1326.8). One hundred five of 223 patients (47.1%) showed detectable BDNF levels, whereas the remainder had no detectable. BDNF positive expression was significantly associated with undifferenciated histological type, lymph node metastasis, and hepatic metastasis. In addition, increased BDNF/TrkB axis expression associated with lymph node metastasis, hepatic metastasis, and peritoneal disseamination. Immunohistochemical analysis indicated intense BDNF expression in the cytoplasm of cancer cells, and intense TrkB expression in the nuclei of cancer cells, respectively. In vitro, administration of recombinant human BDNF promoted proliferation, anoikis resistance, and partial migration. These effects were generally inhibited by Trk antagonist K252a. Conclusions: We demonstrated the clinical and biological function of BDNF/TrkB axis in CRC. BDNF/TrkB axis appears to play an important role in cancer progression, and blocking this pathway might be clinically useful in developing therapies for patients with CRC.
Incidence and patterns of phospho insulin growth factor receptor-1 (pIGF-1R) and matrilysin (MMP7) expression in metastatic colorectal cancer (mCRC), and correlation with KRAS status: A prospective evaluation in the PULSE trial—A GEMCAD study.
Authors: Alonso Vicente , Fernandez-Martos Carlos , Martin Marta , Salud Antonieta , Mendez Jose Carlos , Pericay Carles , Manzano Hermini , Gallego Javier , Horndler Carlos , Machado Isidro , Tobeña Maria , Garcia-Albeniz Xabier , Rubini Michele , Jares Pedro , Cuatrecasas Miriam , Maurel Joan
Published: March 2020

e14041

Background: MMP7 can activate IGF-1R by IGF release due to IGFBP degradation. Activation of IGF-1R can contribute to EGFR resistance by transactivation. We previously described that concomitant expression of p-IGF-1R and MMP7 (Double positive; DP), correlates with poor prognosis, in KRAS WT patients (pts) treated with anti-EGFR compounds (Horndler el al, 2011). Therefore we designed a prospective clinical trial to validate DP as a marker of resistance in KRAS WT pts treated in first-line therapy with FOLFOX-6 plus panitumumab. Methods: mCRC pts in the ongoing prospective PULSE trial (NCT0128833) were prospectively evaluated for p-IGF-1R (p-1316), MMP7 expression and KRAS mutational status. Pts defined as DP should express MMP7 (++ or +++ intensity in >66% of tumor cells) and p-IGF-1R (++ or +++ intensity in >66% of tumor cells). KRAS pts with mutations at exon 2 were excluded. The study was designed to include 40 pts in the two groups (DP vs non-DP) to detect a Hazard ratio difference in PFS of <0.5 (DP vs non-DP) with 80% power. Results: From November 2010 to December 2011, 113 consecutive pts were screened from 24 Spanish Institutions. 54 KRAS WT (40 pts non-DP and 14 DP) have been included. The non-DP arm has being recently closed for inclusion, due to pre-planned complete accrual. Among DP pts, 27% were KRAS WT and 30% KRAS mutant; p=0.63. 48% of cases were positive for p-IGF-1R. Phospho-IGF-1R positive cases had different patterns of staining: peri-nuclear in 76%, 11% nuclear and only 13% membrane-apical staining. These patterns do not differ between KRAS WT; (n=70) and KRAS mutant pts (n=43) (p=0.60). Tumors with positive p-IGF-1R expression, independently of the pattern, have higher MMP7 co-expression (59%) compared with negative cases (13%) (p<0.0001). Conclusions: MMP7 contributes to activate IGF-1R pathway in pts with mCRC. Internalization of the activated IGF-1R, could explain in part, the lack of efficacy of IGF-1R inhibitors in mCRC clinical trials.