Associazione Italiana Per La Ricerca Sul Cancro Research Articles

Circulating biomarkers in familial cerebral cavernous malformation

BackgroundCerebral Cavernous Malformation (CCM) is a rare cerebrovascular disease, characterized by the presence of multiple vascular malformations that may result in intracerebral hemorrhages (ICH), seizure(s), or focal neurological deficits (FND). Familial CCM (fCCM) is due to loss of function mutations in one of the three independent genes KRIT1 (CCM1), Malcavernin (CCM2), or Programmed Cell death 10 (PCDC10/CCM3). The aim of this study was to identify plasma protein biomarkers of fCCM to assess the severity of the disease and predict its progression. MethodsHere, we have investigated plasma samples derived from n=71 symptomatic fCCM patients (40 female/31 male) and n=17 healthy donors (HD) (9 female/8 male) of the Phase 1/2 Treat_CCM trial, using multiplexed protein profiling approaches. FindingsBiomarkers as sCD14 (p= 0.00409), LBP (p= 0.02911), CXCL4 (p= 0.038), ICAM-1 (p= 0.02013), ANG2 (p= 0.026), CCL5 (p= 0.00403), THBS1 (p= 0.0043), CRP (p= 0.0092), and HDL (p= 0.027), were significantly different in fCCM compared to HDs. Of note, sENG (p= 0.011), THBS1 (p= 0.011) and CXCL4 (p= 0.011), were correlated to CCM genotype. sROBO4 (p=0.014), TM (p=0.026) and CRP (p=0.040) were able to predict incident adverse clinical events, such as ICH, FND or seizure. GDF-15, FLT3L, CXCL9, FGF-21 and CDCP1, were identified as predictors of the formation of new MRI-detectable lesions over 2-year follow-up. Furthermore, the functional relevance of ang2, thbs1, robo4 and cdcp1 markers was validated by zebrafish pre-clinical model of fCCM. InterpretationOverall, our study identifies a set of biochemical parameters to predict CCM progression, suggesting biological interpretations and potential therapeutic approaches to CCM disease. FundingItalian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro (AIRC), ERC, Leducq Transatlantic Network of Excellence, Swedish Research Council.

LBA03-12 BIOLOGY AND PERFORMANCE OF PRE- AND POST-PEMBROLIZUMAB (PEMBRO) VESICAL IMAGING-REPORTING AND DATA SYSTEM (VI-RADS) TO PREDICT THE PATHOLOGICAL RESPONSE IN MUSCLE-INVASIVE UROTHELIAL BLADDER CANCER (MIBC): FULL DATA ANALYSIS FROM A CLINICAL TRIALS PIPELINE

LBA03-12 BIOLOGY AND PERFORMANCE OF PRE- AND POST-PEMBROLIZUMAB (PEMBRO) VESICAL IMAGING-REPORTING AND DATA SYSTEM (VI-RADS) TO PREDICT THE PATHOLOGICAL RESPONSE IN MUSCLE-INVASIVE UROTHELIAL BLADDER CANCER (MIBC): FULL DATA ANALYSIS FROM A CLINICAL TRIALS PIPELINE

Circulating Tumor Cells (CTCs) in Smoldering and Active Multiple Myeloma (MM): Mechanism of Egression, Clinical Significance and Therapeutic Endpoints

Circulating Tumor Cells (CTCs) in Smoldering and Active Multiple Myeloma (MM): Mechanism of Egression, Clinical Significance and Therapeutic Endpoints

Sustained Residual Disease Negativity Assessed By Diffusion-Weighted Whole-Body MRI (DW-MRI) Has Strong Predictive Relevance for Survival in Newly Diagnosed Multiple Myeloma Patients on Maintenance Therapy after Autologous Stem Cell Transplantation (ASCT)

Sustained Residual Disease Negativity Assessed By Diffusion-Weighted Whole-Body MRI (DW-MRI) Has Strong Predictive Relevance for Survival in Newly Diagnosed Multiple Myeloma Patients on Maintenance Therapy after Autologous Stem Cell Transplantation (ASCT)

A Screening of Antineoplastic Drugs for Acute Myeloid Leukemia Reveals That Fludarabine Has Weak Immunogenic Capacity and Induces T Regulatory Cells

INTRODUCTION: Recent evidence demonstrated that the treatment of acute myeloid leukemia (AML) cells with Daunorubicin (DNR) but not Cytarabine (Ara-C), results in efficient activation of anti-leukemia T cells. This process, named as immunogenic cell death (ICD), is characterized by some specific events. In the clinical setting, chemotherapy including anthracyclines and Ara-C remains a gold standard for AML treatment. However, the probability of relapse remains elevated, particularly in elderly or prognostically "high risk" patients In the last decade, Etoposide (Eto) and Fludarabine (Flu) have been added to the standard treatment for AML to potentiate its therapeutic effect, and tested in many trials. Regarding the immunogenicity of these two drugs, too few studies are reported in recent literature, and even fewer regarding AML. We therefore studied the immunogenic potential of Eto and Flu as compared to DNR and Ara-C. METHODS: AML cell lines HL-60 and KG-1, and primary AML cells were treated with all four drugs. Calreticulin and heat shock proteins 70/90 translocation, non-histone chromatin-binding protein high mobility group box 1 and adenosine triphosphate release were evaluated. The treated cells were then pulsed into dendritic cells and used forin vitroimmunological tests, in particular for T-cell proliferation and T regulatory cells (Tregs) induction. RESULTS: Collectively, our data indicate that, among the drugs that have been proposed to increase the efficacy of the conventional chemotherapy backbone including DNR and Ara-C, Eto has a similar and comparable capacity to DNR in inducing both early and late ICD events. On the contrary, Flu has a low if any effect, proving similar to Ara-C. Moreover, Eto treatment was the most powerful among the tested drugs in stimulating T-cell proliferation, thus suggesting a significant capacity to activate the immune response. On the contrary, Flu had weak immunogenic potential and can be considered a non-immunogenic chemotherapy drug. Interestingly, Flu was significantly more potent in inducing suppressive T regulatory cells compared to other drugs. CONCLUSIONS: Taken together, the present investigation expands the knowledge on the immunogenic and tolerogenic potential of the chemotherapy drugs commonly used in the therapy of AML. Among these, important differences have been observed, indicating that, particularly in an era when immunotherapy is being included in the clinical stage of AML treatment, the immunological perspective of chemotherapy should be taken into consideration in therapy decision-making. This research was funded by AIRC (Associazione Italiana per la Ricerca sul Cancro) 2017 IG20654. Bologna AIL (Associazione Italiana contro le Leucemie)/ Bologna Section. FATRO/Foundation Corrado and Bruno Maria Zaini-Bologna. Disclosures Cavo: Sanofi:Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Janssen:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau;GlaxoSmithKline:Honoraria, Speakers Bureau;Karyopharm:Honoraria;Novartis:Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Celgene:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau;AbbVie:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;BMS:Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Amgen:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Development of a biomarker-based calculator to predict the probability to achieve a pathologic complete response after neoadjuvant pembrolizumab in muscle-invasive bladder cancer

Abstract Background The PURE01 study (NCT02736266) evaluates preoperative pembrolizumab before radical cystectomy (RC). Here, the possibility to predict the pathologic complete response (pT0) after neoadjuvant immunotherapy could have paradigm-shifting implications for the management of patients with MIBC. Methods The reported analyses include comprehensive genomic profiling with FoundationONE CDx assay and programmed cell-death-ligand-1 (PD-L1) combined positive score (CPS, Dako 22C3 antibody) on baseline TURB samples. Multivariable logistic regression analyses (MVA) evaluated clinical T-stage and biomarkers (tumor mutational burden [TMB], and CPS) in association with pT0 response. Multivariable-derived coefficients were used to develop a novel risk calculator. Decision-curve analysis was used to evaluate the net benefit of the predictive model. Results From 02/2017 to 06/2019, 112 patients with full biomarker data were enrolled. At MVA, only CPS showed a significant association with pT0 (p = 0.005). Increasing TMB and CPS values featured a linear association with logistic pT0 probabilities (p = 0.02 and p = 0.004). Very high TMB values, associated with a predicted probability of pT0 > = 55%, were independent from CPS contribution. The coefficients of the predictive model were used to develop a risk calculator. The c-index of the model was 0.77. At decision-curve analysis, the net-benefit of the model was higher than the “treat-all” option from more than 10% threshold probabilities. Conclusion We presented the first biomarker-based risk stratification tool that can be used to recommend use of neoadjuvant pembrolizumab in those patients who have equal or greater chances to achieve a pT0 status compared to the literature on neoadjuvant chemotherapy or to RC alone, depending on cisplatin eligibility. Clinical trial identification PURE01 study (NCT02736266). Legal entity responsible for the study The authors. Funding Merck & Co., Inc., Kenilworth, NJ, USA; Associazione Italiana per la Ricerca sul Cancro (AIRC). Disclosure R. Madison: Shareholder / Stockholder / Stock options, Full / Part-time employment, employee and stock owner of Foundation Medicine Inc: Foundation Medicine Inc. M. Colecchia: Speaker Bureau / Expert testimony: Roche Diagnostics. S.M. Ali: Full / Part-time employment: Foundation Medicine. J.H. Chung: Full / Part-time employment: Foundation Medicine. J. Ross: Leadership role, Research grant / Funding (institution), Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. A. Salonia: Speaker Bureau / Expert testimony: Astellas Pharma; Travel / Accommodation / Expenses: Konpharma. A. Briganti: Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy: Hanssen-Cilag; Advisory / Consultancy: OPKO Health; Advisory / Consultancy: MDxHealth; Advisory / Consultancy: Ferring; Research grant / Funding (institution): Novartis. A. Necchi: Advisory / Consultancy: Merck, Incyte, AstraZeneca, Roche, Rainier Therapeutics, Clovis Oncology, Bristol-Myers Squibb, Bayer, Basilea Pharmaceutica; Research grant / Funding (institution): AstraZeneca, Ipsen, Merck and Incyte; Spouse / Financial dependant: Bayer. All other authors have declared no conflicts of interest.

28P - GLPG 1790, a new selective EPHA2 inhibitor, is active in colorectal cancer cell lines belonging to the CMS4/mesenchymal-like subtype

BackgroundEPHA2 tyrosine kinase receptor is implicated in tumor progression, stemness phenotype and resistance to treatment in a wide range of cancers. We investigated the effects of GLPG1790, a new selective Eph receptor inhibitor, in colorectal cancer (CRC) across the 4 consensus molecular subtypes (CMS). MethodsWe tested the antiproliferative effect of GLPG 1790 used alone or in combination with either 5-fluorouracil, oxaliplatin or SN38 (the active metabolite of irinotecan) in a panel of 11 CRC cell lines encompassing the 4 consensus molecular subtypes (CMS). Cell cycle analysis was performed in order to understand possible cell cycle perturbation after treatment. Pathway analysis using western blot (WB) was also performed. We then evaluated the expression of stemness genes upon treatment using qRT-PCR. ResultsGLPG 1790 is active in CRC cell lines, with the strongest activity in the cell lines from the CMS4/mesenchymal-like cluster. Combination with chemotherapeutics is not synergistic according to Chou-Talalay model. The selective inhibitor elicits a persistent inactivation of EPHA2 receptor, associated to G0-G1 cell cycle block in the sensitive cell lines. Furthermore, GLPG 1790 is able to decrease the expression of cancer stem cell genes in cell lines belonging to the CMS4 group. ConclusionsEPHA2 blockade using the selective inhibitor GLPG 1790 has a strong antiproliferative effect in the chemorefractory subgroup of CMS4/mesenchymal-like CRC cell lines, associated to a G0-G1 cell cycle arrest.The stronger efficacy of GLPG1790 on the mesenchymal-like subtype is probably due to the impairment of cancer cell stemness and induction of cell differentiation after treatment. Legal entity responsible for the studyThe authors. FundingUniversità della Campania "Luigi Vanvitelli"; Galapagos NV (drug supply); Associazione Italiana per la Ricerca sul Cancro (AIRC). DisclosureP.P. Vitiello: Travel/Accommodation/Expenses: Amgen; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Servier; Research grant/Funding (institution): Ipsen; Travel/Accommodation/Expenses: BMS; Travel/Accommodation/Expenses: Sanofi. C. Cardone: Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Ipsen; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Roche. D. Ciardiello: Travel/Accommodation/Expenses: Sanofi. L. Poliero: Travel/Accommodation/Expenses: BMS. C. Borrelli: Travel/Accommodation/Expenses: BMS. N. Zanaletti: Travel/Accommodation/Expenses: BMS. P. Vitale: Travel/Accommodation/Expenses: BMS. T. Troiani: Honoraria (self), Research grant/Funding (institution): Roche; Honoraria (self), Research grant/Funding (institution): Merck; Honoraria (self), Research grant/Funding (institution): Bayer; Honoraria (self), Travel/Accommodation/Expenses: Amgen; Travel/Accommodation/Expenses: Servier; Travel/Accommodation/Expenses: Sanofi; Travel/Accommodation/Expenses: Novartis. F. Ciardiello: Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy: Servier; Advisory/Consultancy: Pfizer; Research grant/Funding (institution): Ipsen. E. Martinelli: Honoraria (self), Research grant/Funding (institution): Amgen; Honoraria (self), Research grant/Funding (institution): Merck; Honoraria (self), Research grant/Funding (institution): Bayer; Honoraria (self), Research grant/Funding (institution): Roche; Honoraria (self), Honoraria (institution): Servier. All other authors have declared no conflicts of interest.

55P - Synergistic activity between niraparib and chemotherapy in colorectal cancer: Molecular determinants from a preclinical model

BackgroundPoly-ADP-Ribose Polymerase inhibitors (PARPi) constitute a class of drugs that interfere with DNA damage response and are already available or in current advanced development either alone or in combination with DNA damaging agents such as chemotherapeutics. Some features of colorectal cancer (CRC), like microsatellite instability and MAPK-induced replication stress, make it a good candidate for exploring the combination of PARPi with chemotherapeutics. Previous data have evidenced how PARPi/chemotherapy combinations are effective in various cancers, albeit early clinical trials showed only modest activity in unselected CRC patients. MethodsWe tested the activity of the PARPi niraparib (MK-4827) used alone or in combination with either 5-fluorouracil, oxaliplatin or irinotecan (SN38) in a panel of 12 CRC cell lines with known molecular characteristics. Proliferation, cell cycle and apoptosis assays were performed. A correlation between combination synergism and the following molecular features was obtained: RAS/BRAF mutation, HER2 amplification, microsatellite status, mutational and transcriptomic profiles from the Cancer Cell Line Encyclopedia (CCLE) database. Mice xenografts using the most representative cell lines are ongoing. Patient-derived 3D primary cultures (PDPCs) are being used to confirm the data obtained in vitro. ResultsNiraparib is synergistic with the investigated chemotherapeutics in most of the cell lines explored. The best candidate for combination is SN38, which is synergistic in 9/12 cell lines analysed. MAPK activation, microsatellite instability (MSI) and mutations in genes involved in homologous recombination repair (HRR) are good predictors of synergism. Transcriptomic analysis is ongoing. Mice xenografts and PDPCs models are in progress and will be presented at the Congress. ConclusionsThe combination of niraparib and irinotecan/SN38 is effective in an in vitro model of CRC. MAPK activation, MSI and mutation in HRR-associated genes are predictors of synergism and are currently being validated in in vivo and ex vivo models. These findings could lead to a better patient selection for this combination in CRC. Legal entity responsible for the studyThe authors. FundingUniversità della Campania Luigi Vanvitelli; Associazione Italiana per la Ricerca sul Cancro (AIRC). DisclosureP.P. Vitiello: Research grant/Funding (institution), Travel/Accommodation/Expenses: Amgen; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Ipsen; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Roche; Travel/Accommodation/Expenses: BMS; Travel/Accommodation/Expenses: Sanofi-Genzyme. D. Ciardiello: Travel/Accommodation/Expenses: Sanofi. C. Cardone: Research grant/Funding (institution): Ipsen; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Bayer. G. Martini: Research grant/Funding (self): Amgen. C. Borrelli: Travel/Accommodation/Expenses: BMS. L. Poliero: Travel/Accommodation/Expenses: BMS. V. De Falco: Travel/Accommodation/Expenses: BMS; Travel/Accommodation/Expenses: Novartis. E.F. Giunta: Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: BMS. M. Terminiello: Travel/Accommodation/Expenses: BMS. T. Troiani: Research grant/Funding (institution): Roche; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Bayer; Travel/Accommodation/Expenses: Servier; Travel/Accommodation/Expenses: Amgen; Travel/Accommodation/Expenses: Sanofi; Travel/Accommodation/Expenses: Novartis. F. Ciardiello: Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy: Servier; Advisory/Consultancy: Pfizer; Research grant/Funding (institution): Ipsen. E. Martinelli: Honoraria (self), Research grant/Funding (institution): Amgen; Honoraria (self), Research grant/Funding (institution): Bayer; Honoraria (self), Research grant/Funding (institution): Merck; Research grant/Funding (institution): Roche; Honoraria (self), Research grant/Funding (institution): Servier. All other authors have declared no conflicts of interest.

LBA35 - Phase II study of pertuzumab and trastuzumab-emtansine (T-DM1) in patients with HER2-positive metastatic colorectal cancer: The HERACLES-B (HER2 Amplification for Colo-rectaL cancer Enhanced Stratification, cohort B) trial

BackgroundHER2 amplification (HER2+) is a therapeutic target for 2% (unselected)-6% (RAS wild-type) metastatic colorectal cancer (mCRC). In the HERACLES-A Trial of trastuzumab and lapatinib (Lancet Oncology, 2016), HER2+ KRAS wild-type mCRC patients achieved an overall objective response rate (CR+PR = ORR) of 30%. Based on this result and on preclinical trials, we activated HERACLES-B, evaluating a targeted chemotherapy precision approach by combining pertuzumab with T-DM1. MethodsHERACLES-B is an open-label phase II trial in RAS/BRAF wild-type HER2+ mCRCs (as defined in Valtorta et al, 2015). ORR and Progression-Free Survival (PFS) are the primary and secondary end-points, respectively. With a Fleming/Hern design (H0=ORR 10%; α=0.05; power=0.85), 7 OR/30 were required to demonstrate an ORR ≥30% (H1). Main inclusion criteria were: PS 0-1, progression after 5FU, oxaliplatin, irinotecan, and anti-EGFR containing regimens. Pertuzumab was dosed at 840mg iv load, followed by 420mg iv q3 weeks and T-DM1 at 3.6mg/Kg q3 weeks. NGS-based molecular analyses of tumor tissue/plasma were performed. ResultsFrom 8/2016 to 3/2018, 30 patients were enrolled, treated and evaluable for efficacy. Patients received a median of 3 prior regimens. Data lock and centralized radiological revision were completed by 30/7/2019. ORR was 10% [95% CI: 0-28] and stable disease (SD) 70% [95% CI: 50-85]. Median PFS was 4.8 mos. [95% CI: 3.6-5.8]. Higher HER2 IHC score (3+ vs 2+) was associated with objective response/SD ≥4 mos. [p=0.03]. Drug-related G3 adverse events were observed only in 2 patients (thrombocytopenia); G≤2 events in 84% of cycles (N=296), mainly nausea and fatigue. ConclusionsAlthough HERACLES-B did not reach its primary endpoint, disease control was achieved in 80% of patients with a median PFS of 4.8 mos. that is superimposable to the 4.2 mos. achieved in the positive HERACLES-A trial. While the ORR could have been weakened by the lower trastuzumab dose delivered with T-DM1, the retained favorable PFS might be due the combined ‘broad-brush’ effect of emtansine and the synergy with pertuzumab. Preliminary molecular results will be presented. Clinical trial identificationEudraCT: 2012-002128-33. Legal entity responsible for the studyFondazione del Piemonte per l’Oncologia IRCC di Candiolo. FundingFondazione Piemontese per l’Oncologia - FPO funded by Associazione Italiana per la Ricerca sul Cancro (AIRC). Roche provided pertuzumab and T-DM1 for free. DisclosureA. Sartore-Bianchi: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Sanofi. A. Amatu: Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy: Amgen. A. Ardizzoni: Advisory / Consultancy: Roche. L. Trusolino: Research grant / Funding (self): Symphogen; Research grant / Funding (self): Merus; Research grant / Funding (self): Servier; Research grant / Funding (self): Pfizer; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Merck KGaA. S. Siena: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy: CheckMab; Advisory / Consultancy: Celgene; Advisory / Consultancy: Clovis; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Incyte; Advisory / Consultancy: Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche-Genentec; Advisory / Consultancy: Seattle Genetics. All other authors have declared no conflicts of interest.

Abstract P3-10-02: Presence of atypia in ductal lavage and risk of subsequent breast cancer in a prospective study

Abstract Background: Atypical hyperplasia is considered a nearly obligate precursor of breast cancer and is associated with a higher risk of developing breast cancer (BC). Attempts to improve early detection of breast cancer and to provide individualized breast cancer risk assessment would greatly benefit from sampling cellular material from the target tissue. Ductal lavage (DL) is a minimally invasive technique which provides adequate material to detect atypical cells in mammary ducts. However, long term data of the association between atypia from ductal lavage and BC risk are lacking. We studied the prevalence of atypia in DL in different risk categories and its ability to predict BC development in women at risk. Methods: From March 2000 to July 2012 we performed DL in a consecutive series of 348 women with median age of 45 years (range 19-74) at increased BC risk based on the following characteristics: 5 yrs Gail model > 1.66% or > 10% probability of BRCA mutation (n = 155), history of contralateral BC (CBC, n = 161), presence of a BRCA pathogenic variant (n = 32). We analyzed the presence of atypical cells in the baseline specimen of ductal lavage and in repeated lavage and observed their evolution during follow-up. Results: The procedure was safe and well tolerated in most women, with pain and disconfort preventing the procedure in 5.4% of subjects. Overall, 126 (36%) women had atypia at baseline, with a prevalence of 32%, 39%, and 41% in the Gail, CBC and BRCA groups, respectively (p = 0.38). The overall prevalence of atypia considering all visits was 44% (range 36-51). After a median follow up of 6 years, cumulative BC events were 8% in women without atypia versus 14% in those with atypia (log-rank p = 0.08). In the highest risk groups (CBC and BRCA pathogenic variants), the number of BC events was 16 (21%) in women with atypia versus 11 (10%) in women without atypia (p = 0.02 after adjustment for age). Conclusions: Our findings suggest that cytologic atypia in the fluid obtained by DL predicts subsequent BC in women at increased risk, providing individual risk assessment. The reversal of atypia in DL should be evaluated as a surrogate biomarker of BC therapeutic prevention. Supported by: Associazione Italiana per la Ricerca sul Cancro (AIRC), Lega Italina per la Lotta contro i Tumori (LILT), AVON Foundation for Women. Citation Format: De Censi A, Cazzaniga M, Gandini S, Casadio C, Chiapparini L, Guerrieri-Gonzaga A, Macis D, Veronesi P, Bonanni B. Presence of atypia in ductal lavage and risk of subsequent breast cancer in a prospective study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-10-02.

Pembrolizumab as Neoadjuvant Therapy Preceding Radical Cystectomy in Patients with Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Group, Phase 2 Study

Background: Cisplatin-based neoadjuvant chemotherapy prior to radical cystectomy (RC) is the standard of care for muscle-invasive bladder carcinoma (MIBC), but it is administered in few patients. Methods:In the PURE-01 study, pembrolizumab was administered prior to RC. The patients had a predominant urothelial carcinoma histology and clinical (c)T≤3bN0 stage. They received 3 cycles of 200 mg pembrolizumab every 3 weeks prior to RC. Pathologic complete response (pT0) in intention-to-treat population was the primary endpoint. The biomarker analyses included PD-L1 expression using the combined positive score (CPS) (Dako 22C3), genomic sequencing (FoundationOne assay) and an immune gene expression assay. Findings: From 02/17 to 03/18, 50 patients were enrolled. Twenty-seven (54%) had cT3, 21 (42%) had cT2, and 2 (4%) had cT2-3N1. One patient (2%) had a grade 3 transaminase increase and discontinued pembrolizumab. All patients underwent RC: there were 21 pT0 (42%, 95% CI: 29*4-55*8%). As a secondary endpoint, the downstaging to pT<2 was obtained in 27 patients (54%, 95% CI: 40*4-67%). In 54.3% of the patients with PD-L1 CPS≥10% (n=35), RC indicated pT0, whereas RC indicated pT0 in only 13*3% of those with a CPS<10% (n=15). All 5 patients with a tumor mutation burden (TMB) in the 90th percentile achieved pT0. The expression of several genes in pre-therapy lesions was significantly different between pT0 and non-pT0 cohorts. Significant post-therapy changes in the TMB and evidence of adaptive mechanisms of immune-resistance were observed in residual tumors. Interpretation: Neoadjuvant pembrolizumab resulted in 42% pT0 and was safely administered in MIBC patients. This study supports that pembrolizumab could be a worthwhile neoadjuvant therapy for MIBC when limited to patients with PD-L1-positive or high-TMB tumors. Clinical Trial Number: ClinicalTrials.gov, number NCT02736266 Funding Statement: Merck & Co., Inc., Kenilworth, NJ, USA; Associazione Italiana per la Ricerca sul Cancro (AIRC). Declaration of Interests: Necchi A: consultant for Merck, Astra Zeneca, Janssen, Incyte, Roche, BioclinTherapeutics, Clovis Oncology, Bayer, and Astellas/Seattle Genetics. Grant/Research support from: Merck and Astra Zeneca. Travel expenses/Honoraria from: Roche, Merck, Astra Zeneca, and Janssen. Ali SM, Madison R, Ross JS, and Chung JH: employees of Foundation Medicine Inc. Raggi D, Anichini A, Giannatempo P, Briganti A, Massa S, Luciano R, Colecchia M, Mortarini R, Bianchi M, Colombo R, Gallina A, Salonia A, Messina A, Salvioni R, and Montorsi F: no disclosures. Ethics Approval Statement: The study protocol and all amendments were approved by the ethics committee of the sponsor institution. The study was conducted in accordance with the protocol and its amendments, the Good Clinical Practice guidelines, and the provisions of the Declaration of Helsinki. All patients provided written informed consent before enrollment.

Abstract 1922: miR-301 expression is deregulated in rhabdomyosarcoma

Abstract Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma of myogenic derivation. Conversely to normal myoblasts, RMS cells are unable to differentiate, thus they proliferate indefinitely. MicroRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression by affecting both the stability and translation of mRNAs. They are fundamental regulators of myogenesis and their deregulation has been involved in the pathogenesis of RMS. We evaluate here the expression and regulation of miR-301, which has been related to tumorigenesis in other types of cancers. We report here that the expression of miR-301 is upregulated in primary samples of both the alveolar RMS, which bears the fusion protein PAX3-FOXO1 (P3F) (ARMS), and the fusion-negative embryonal RMS (ERMS) compared to normal muscle tissues. Similarly, it appears higher in RMS cell lines versus normal skeletal myoblasts. Using an inhibitor of miR-301 (CONTRAmiR) we demonstrate that this miRNA favors RMS cell mobility and down-regulates p21Cip1, PTEN and DICER1 levels. However, the inhibition of miR-301 with the CONTRAmiR does not reduce tumor cell proliferation suggesting that the regulation of cell cycle is not under the control of this miRNA in RMS. Interestingly, the expression of SKA2 (Spindle And Kinetochore Associated Complex Subunit 2), whose gene hosts miR-301, is also upregulated in our setting. Experiments are ongoing to determine whether miR-301 and SKA2 are associated with RMS pathogenesis and could be targets for an anti-RMS therapy. This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC). Citation Format: Rossella Rota, Alberto Gualtieri, Cristina Cossetti, Silvia Pomella, Laura Adesso, Franco Locatelli. miR-301 expression is deregulated in rhabdomyosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1922.

PO-15 - Antiangiogenic small molecule ligands of FGF2 derived from the endogenous inhibitor thrombospondin-1

Platelet thrombospondin-1 (TSP-1) is a major endogenous regulator of growth factor activity in physiological and pathological processes, including tumor onset, progression and angiogenesis. We previously demonstrated that TSP-1 binds to FGF-2, sequestering the growth factor and inhibiting its angiogenic activity. We also identified a non-peptidic antiangiogenic compound (SM27) that retains the structural and functional properties of the FGF2-binding sequence of TSP-1. To identify new small molecule inhibitors of FGF2 that recapitulate the structure and functional properties of the FGF-2-binding site of TSP-1, by investigating the chemical space around SM27. A similarity-based screening of small molecule libraries has been used to identify candidates, followed by docking calculations, and evaluation of the activity of the resulting compounds in biochemical and biophysical assays, to assess interaction with FGF2, and in experimental models of angiogenesis, to assess biological activity. The used integrated approach allowed selecting 7 bi-naphthalenic compounds that bound FGF2 inhibiting FGF2 binding to both heparan sulfate proteoglycans and FGFR1. The compounds inhibited FGF2-induced endothelial cell proliferation, vessel sprouting from aortic rings and angiogenesis in the chorioallantoic membrane assay, with improved potency over SM27. We have identified new compounds that are valuable as FGF inhibitors for potential therapeutic purposes. Moreover, these compounds are useful chemical tools to identify the minimal stereochemical requirements for FGF2 binding and activity to improve the design of new agents for antineoplastic therapy. Supported by AIRC (Associazione Italiana per la Ricerca sul Cancro).

Abstract 4945: A novel role for drebrin in regulating progranulin bioactivity in bladder cancer

Abstract Bladder cancer (BC) is one of the most common cancers in the United States with 56,390 estimated new cases and 11,170 estimated deaths in 2014. The majority of deaths is due to metastatic spread. Understanding the molecular mechanisms regulating bladder tumor cell invasion and progression toward metastases is essential for developing better therapies to treat bladder cancer patients. The growth factor progranulin plays an important role in cell proliferation, wound healing and transformation. We have recently established a critical role for progranulin in bladder cancer insofar as progranulin promotes urothelial cancer cell motility and contributes, as an autocrine growth factor, to the transformed phenotype by modulating invasion and anchorage-independent growth. In addition, progranulin expression is upregulated in invasive bladder cancer tissues compared to normal controls. However, the molecular mechanisms of progranulin action in bladder cancer have not been fully elucidated. In this study, we searched for novel progranulin-interacting proteins using pull-down assays with recombinant progranulin and proteomics. We discovered that drebrin, an F-actin binding protein, bound progranulin in urothelial cancer cells. We characterized drebrin function in various urothelial cancer cell lines and showed that drebrin is critical for progranulin-dependent activation of the Akt and MAPK pathways and modulates F-actin remodeling, motility, invasion and anchorage-independent growth. In addition, drebrin regulates tumor formation in vivo and its expression is upregulated in bladder cancer tissues compared to normal tissue controls. Our data are translationally relevant as indicate that drebrin exerts an essential functional role in the regulation of progranulin action and may constitute a novel target for therapeutic intervention in bladder tumors. In addition, drebrin may serve as novel biomarker for bladder cancer. This work was supported by the Benjamin Perkins Bladder Cancer Fund, National Institutes of Health Grants RO1 CA164462 (A.M., R.V.I.), and RO1 CA39481 and RO1 CA47282 (R.V.I.), Associazione Italiana per la Ricerca sul Cancro (AIRC) (grant n. 10625/12), AIRC project Calabria 2014 and Fondazione Cassa di Risparmio di Calabria e Lucania PON01_01078 (A.B.). Alaide Morcavallo was supported in part by Fondazione Diabete Ricerca. Citation Format: Shi-Qiong Xu, Simone Buraschi, Alaide Morcavallo, Marco Genua, Tomoaki Shirao, Stephen C. Peiper, Leonard G. Gomella, Antonino Belfiore, Renato V. Iozzo, Andrea Morrione. A novel role for drebrin in regulating progranulin bioactivity in bladder cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4945. doi:10.1158/1538-7445.AM2015-4945

Isolation, Expansion and Characterization of BM-Mesenchimal Cells (MSCs) in Patients Affected By Chronic Myeloproliferative neoplasm (MPN)

Introduction MSCs constitute a pivotal cell type capable of shaping both the architecture of the microenvironment and modulating communication between the various cell types through effects on the extracellular matrix (ECM) and by secretion of various growth factors and cytokines. MSCs and hematopoietic stem cells are thought to share the same mesenchymal origin. Some data confirm that MSCs express a functional erythropoietin receptor and JAK2-transduction pathway, but their role in the development and evolution of MPN is still not well known so our aim was the isolation, expansion and characterization of MSCs in patients affected by MPN. Some data indicates that BM-MSCs of patients affected by MPN do not carry the JAK2-V617F mutation. We studied 20 patients affected by MPN with the following characteristics: M/F 12/8, median age 53years, 8 affected by PV, 8 by ET and 4 by PMF. 15 patients were positive for JAK2 V617F mutation, 1 pts for cMPL and 2 were CARL mutations carriers.Methods: MSC were isolated by bone marrow fraction by gradient separation on Lympholyte cell separation media and expanded in culture with a specific medium (MesenCult) in plastic-adherent cultures up to the second passage. DNA was extracted from MSC using QIAmp DNA Mini kit and the study of recurrent alterations (JAK2, MPL and CARL gene mutations was performed).Results: MCS were expanded in 14 on 21 patients. Flow citometry analysis confirmed the standard MSC phenotype (CD45 negative, CD73 positive, CD90 positive and CD105 positive). The molecular analysis of JAKV617F, cMPL and CARL mutations resulted negative in all analyzed samples both in patients carriers of mutations and in wild type ones.Conclusions: We conclude that common mutations markers of MPN neoplasm are absent in the mesenchymal compartment of bone marrows of patients affected by MPN and are restricted to the neoplastic clone.This research project was supported by a grant from Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.) DisclosuresNo relevant conflicts of interest to declare.

Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association

Congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease and they are the most frequent cause of end-stage renal disease in children in the US. However, its genetic etiology remains mostly elusive. VACTERL association is a rare disorder that involves congenital abnormalities in multiple organs including the kidney and urinary tract in up to 60% of the cases. By homozygosity mapping and whole exome resequencing combined with high-throughput mutation analysis by array-based multiplex PCR and next-generation sequencing, we identified recessive mutations in the gene TNF receptor-associated protein 1 (TRAP1) in two families with isolated CAKUT and three families with VACTERL association. TRAP1 is a heat shock protein 90-related mitochondrial chaperone possibly involved in antiapoptotic and endoplasmic reticulum-stress signaling. Trap1 is expressed in renal epithelia of developing mouse kidney E13.5 and in the kidney of adult rats, most prominently in proximal tubules and in thick medullary ascending limbs of Henle’s loop. Thus, we identified mutations in TRAP1 as highly likely causing CAKUT or CAKUT in VACTERL association.

JAK2 (V617F)-Positive Essential Thrombocythemia and Polycythemia Vera Are Different Expressions Of a Genotypic/Phenotypic Continuum

BackgroundAbout 95% of patients with polycythemia vera (PV) and 60-70% of those with essential thrombocythemia (ET) carry the unique JAK2 (V617F) mutation. Previous observations suggest that JAK2 (V617F)-positive ET and PV form a biological continuum, in which the degree of erythrocytosis is determined by physiological and genetic factors. AimsIn this work, we studied the natural history of JAK2 (V617F)-positive ET and PV with the aim of establishing whether the two disorders indeed represent different phenotypic expression of a genotypic/phenotypic continuum. MethodsWe identified 1269 patients diagnosed with ET or PV at our Division between 1980 and 2012, for whom at least one DNA sample was available. The JAK2 (V617F) mutation was assessed using allele-specific quantitative PCR. As patients carrying JAK2 exon 12 or MPL mutations were excluded, the final study population included 1214 patients, 719 of whom with ET (463 JAK2 mutated, 256 JAK2 wild-type) and 495 with PV. ResultsI: presenting featuresThe clinical phenotype of ET patients at diagnosis differed according to JAK2 mutational status. JAK2 mutated ET presented with older age at diagnosis, higher hemoglobin (Hb) level and white blood cell (WBC) count, lower platelet (PLT) count and erythropoietin level compared to JAK2 wild-type ET (Wilcoxon rank-sum test: P<.001 in all comparisons).The median V617F allele burden was significantly lower in JAK2 mutated ET than in PV (18.4% vs 43.4%, P<.001). A mutant allele burden greater than 50% was observed in 2% of patients with JAK2 mutated ET and 41.5% of those with PV (Fisher exact test: P<.001). In both JAK2 mutated ET and PV, the mutant allele burden was directly related to WBC count and Hb level. ResultsII: PV evolutionEvolution to PV was observed in 53 JAK2 mutated ET patients (incidence 95% CI: 1.4-2.4 per 100 p-years) vs none of the 256 JAK2 wild-type ET (incidence 95% CI: 0-0.2 per 100 p-years), resulting in a significantly different occurrence. The median time to PV evolution was 54 months (range 3.5-220). The cumulative incidence of PV evolution in JAK2 mutated ET patients at 15 years was 28.8% (95% CI: 20.7-37.3; Figure 1). PV evolution was significantly associated with higher JAK2 allele burden at diagnosis (Cox regression HR=1.04, P<.001). [Display omitted] Based on the hypothesis that PV patients might have had a silent “pre-PV phase”, we did an ad hoc search for any complete blood count (CBC) collected before diagnosis. Among PV patients, 177 (36%) had a previous CBC, collected at a median time of 22 months (range 1-305) before PV diagnosis. A normal CBC was observed in 15% of patients; the remaining subjects showed thrombocytosis (≥450 x 109/L) and/or leukocytosis (≥10 x 109/L) and/or erythrocytosis. The median time to PV onset was significantly shorter in patients showing at least one CBC abnormality than in those with normal CBC (24 vs 48 months, P=.011). ResultsIII: clinical courseThe median follow-up was 5.1 years (range, 0-32 years). JAK2-mutated ET and PV did not differ in terms of cumulative incidence of thrombosis (25.3% vs 33.7% at 15 years, P=.35; Figure 2A) and had similar overall survival (OS) (90.3% vs 82.6% at 15 years, P=.29; Figure 2B). Conversely, JAK2 wild-type ET showed a better OS in comparison with both JAK2 mutated ET (P=.028) and PV (P=.004) and a lower incidence of thrombosis (12.7% at 15 years) than JAK2 mutated ET (P=.002) and PV (P<.001). [Display omitted] [Display omitted] A similar cumulative incidence of disease progression (leukemia and myelofibrosis) was observed in JAK2 mutated (11.7% at 15 years) and JAK2 wild-type ET (12.1% at 15 years), whereas a higher cumulative incidence was observed in PV (26% at 15 years; P=.011 and P=.007 when compared with JAK2 mutated ET and JAK2 wild-type ET respectively). ConclusionsThis study supports the hypothesis that JAK2 mutated ET and PV are different expressions of a genotypic/phenotypic continuum, in which the mutant allele burden contributes to determine the clinical phenotype. The risk of progression from JAK2 mutated ET to PV is about 2% per year.This work was supported by grant #1005 from Associazione Italiana per la Ricerca sul Cancro (AIRC) “Special Program Molecular Clinical Oncology 5x1000” to AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative - http:www-progettoagimm.it). Disclosures:No relevant conflicts of interest to declare.

Beneficial effect of directional freezing on in vitro viability of cryopreserved sheep whole ovaries and ovarian cortical slices

Does directional freezing improve the structural and functional integrity of ovarian fragments compared with conventional slow freezing and to whole ovary cryopreservation? Compared with slow freezing, the use of directional freezing significantly improves all structural and functional parameters of ovarian fragments assessed in vitro and, overall, whole ovaries were better preserved than ovarian fragments. Directional freezing has been developed to provide an alternative way to cryopreserve large biological samples and it is known to improve the structural and functional integrity of whole ovaries. Conventional slow freezing of ovarian fragments is the procedure more widely used in clinical settings but it causes substantial structural damage that limits the functional period after transfer back into the patient. We performed a 2 × 2 factorial design experiment on a total of 40 sheep ovaries, divided into four groups (n = 10 ovaries per group): (i) directional freezing of whole ovary (DFwo); (ii) directional freezing of ovarian fragments (DFof); (iii) conventional freezing of whole ovary (CFwo); (iv) conventional freezing of ovarian fragments (CFof). An additional eight ovaries were used as fresh controls. Ewe ovaries were randomly assigned to one of the experimental groups and frozen accordingly. Upon thawing, ovarian tissue was examined morphologically and cultured in vitro for 7 days. Samples were analyzed for cell proliferation and apoptosis, for DNA damage and repair activity, and for the presence of a panel of heat shock proteins (HSPs) by immunohistochemistry. Most studied parameters were significantly improved (P < 0.05) in all samples cryopreserved with directional compared with slow freezing. The proportion of primordial follicles, which developed to the primary stage in whole ovaries (53 ± 1.7%) and in ovarian fragments (44 ± 1.8%) cryopreserved with directional freezing, was greater than with slow frozen whole ovaries (6 ± 0.5%, P = 0.001) or fragments (32 ± 1.5%, P = 0.004). After 7 days of culture, cell proliferation in DFwo (28 ± 0.73%) was the highest of all groups (P < 0.05) followed by DFof (23 ± 0.81%), CFof (20 ± 0.79%) and CFwo (9 ± 0.85%). Directional freezing also resulted in a better preservation of the cell capacity to repair DNA damage compared with slow freezing both in whole ovaries and ovarian fragments. Apoptosis and HSP protein levels were significantly increased only in the CFwo group. Direct comparison demonstrated that, overall, DFwo had better parameters than DFof and was no different from the fresh controls. The study is limited to an in vitro evaluation and uses sheep ovaries, which are smaller than human ovaries and therefore may withstand the procedures better. Improved integrity of ovarian morphology may translate to improved outcomes after transplantation. Alternatively, the particularly good preservation of whole ovaries suggests they could provide a source of ovarian follicles for in vitro culture in those cases when the presence of malignant cells poses a substantial risk for the patient. Supported by: Associazione Italiana per la Ricerca sul Cancro (AIRC) IG 10376, Carraresi Foundation and by Legge 7 Regione Autonoma Sardegna (R.A.S). There are no conflicts of interest.

Abstract A76: EGFR activation signaling cascade leads to phosphorylation on serine 732 of FAK and mitosis in a subset of epithelial ovarian cancer

Abstract The epidermal growth factor receptor (EGFR) is expressed in up to 70% of epithelial ovarian cancer (EOC) where it correlates with poor prognosis. Despite the evidence for EGFR expression in the majority of EOCs, to date a uniform picture of the biological and clinical consequences of EGFR expression and activation has not emerged. Indeed, treatment of EOC patients with anti-EGFR results in a very poor response and is not correlated to EGFR expression. We aimed to characterize EGFR-expressing EOCs in the aim to better define EGFR-expressing EOC subtypes. We have recently showed that co-expression as well as the concomitant presence of IL-6 and PAI-1 in EOC ascites could characterize a subset of EGFR-expressing EOCs with shorter progression-free survival after chemotherapy. In vitro we have also found that the EOC cell line resembling this subset of EOC is more sensitive to anti-EGFR compounds suggesting that the association of anti-EGFR agents with taxol and cisplatin could be more appropriate for treating this subset of EOCs. We are now further investigating EGFR signaling cascade in EOC cell lines not only in traditional 2D cultures but also in 3D culture. Indeed, we found that in EOC E-cadherin (cadh) may be still present at cell-cell contacts during tumor progression and that EOC cells present in the ascites preferentially express E-cadh at cell-cell contacts. Therefore, we have set up a 3D culture system, resembling the multicellular aggregates (MCAs) found in the ascites, by using a commercially available alginate matrix to which human cells do not attach. Immunoblotting on 3D EOC cell line showed a significant increase of E-cadh expression together with that of cytokeratin 8/18 and vimentin. Interestingly, in this system we found a tremendous increase of EGFR phosphorylation and that EGF stimulation induced EGFR phosphorylation and triggered PI3K/AKT and MEK/ERK activations. In line with these results, down-modulation of E-cadh expression by specific siRNA, was associated with a significant decrease of EGFR phosphorylation with consequent decrease of both AKT and MAPK phosphorylations. Interestingly, EGF stimulation led to phosphorylation (P-) of FAK on tyrosine residues and also on FAK at Ser-732 (FakSer732). In vivo, in E-cadh-expressing EOC cells present in the ascites P-FAKser732 was also present. In vitro P-FAKSer732 was barely detectable during interphase while its levels strongly increased in mitotic cells upon activation of the EGFR/MEK/ERK axis in an integrin-independent manner. P-FAKSer732 presence was crucial for the maintenance of the proliferation rate and its level was inversely related to the level of acetylated α-tubulin. P-FAKSer732 localized at the microtubules (MT) of the spindle, biochemically associated with MT and contributed to MT depolymerization. The lack of the phosphorylation on Ser732 as well as the inhibition of CDK5 activity by roscovitine impaired mitotic spindle assembly and correct chromosome alignment during mitosis. In conclusion, we have identified that the EGF-dependent EGFR activation led to increased P-FAKSer732 and polymerized MT. Our data shed light on the multifunctional roles of FAK in neoplastic cells, being involved not only in integrin-dependent migratory signaling, but even in integrin-independent MT dynamics and mitosis control. These findings provide a new potential target for inhibiting the growth of EOC cells in which the EGFR/MEK/ERK/CDK5 pathway is active. Partially supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) Citation Format: Antonella Tomassetti, Katia Rea, Marialuisa Sensi, Silvana Canevari. EGFR activation signaling cascade leads to phosphorylation on serine 732 of FAK and mitosis in a subset of epithelial ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A76.

L-GILZ forms a complex with p53 and mdm2 and suppresses tumor growth through p53 activation

L-GILZ forms a complex with p53 and mdm2 and suppresses tumor growth through p53 activation