Browsing Over 126 Presentations
Q&A (ID 265)
7P - Proteomics plus RNA-seq in advanced melanoma samples treated with anti-PD1 immunotherapy unravel resistance mechanisms (ID 215)
- Guillermo Prado (Madrid, Spain)
- Guillermo Prado (Madrid, Spain)
- Angelo Gámez Pozo (Madrid, Spain)
- Lucía Trilla Fuertes (Madrid, Spain)
- Andrea Zapater Moros (Madrid, Spain)
- Elena López Camacho (Madrid, Spain)
- Rocío López Vacas (Madrid, Spain)
- Mariana Díaz Almirón (Madrid, Spain)
- Pilar Zamora (Madrid, Spain)
- Juan Angel Fresno Vara (Madrid, Spain)
- Enrique Espinosa (Madrid, Spain)
Abstract
Background
Melanoma is the most lethal malignancy of the skin. Immunotherapy has contributed to improved survival in melanoma patients, yet the mechanisms explaining differences in efficacy have not been elucidated. In previous studies our group found an immune signature that predicts response to antiPD1 immunotherapy. On the other hand, melanoma genomics have been extensively studied, but data regarding protein expression are still scarce. We have performed a genomics plus proteomics analysis of advanced melanoma samples aiming to find mechanisms of resistance to antiPD1.
Methods
53 formalin-fixed, paraffin-embedded (FFPE) melanoma samples were analyzed using a high-throughput proteomics approach based on mass-spectrometry. Using the same 53 FFPE samples we performed RNA-seq of 2000 preselected genes through SeqCap® RNA Choice Probes. Both proteomics and RNA-seq data will be analyzed using probabilistic graphical models (PGM) and sparse-k means plus consensus cluster algorithm, independently and joint together.
Results
53 advanced melanoma patients treated with anti-PD1 immunotherapy were recruited. Proteomics analyses allowed the identification and quantification of 1605 proteins passing quality criteria (two unique peptides and less than 50% of missing values). A PGM, including these 1605 proteins was built, and the resulting graph was processed to seek for functional structures. Successive sparse k-means and consensus cluster algorithm were performed to find the different informative layers. We found an informative layer composed of 102 proteins that divide patients in two groups; these two groups had prognostic value. On the other hand, a PGM including the 2000 genes will be also built (experiments already ongoing). Finally, results from both proteomics and genomics approach will be combined looking for anti-PD1 resistance mechanisms.
Conclusion
The integration of different omics will lead us to a better understanding of the resistance mechanisms to anti-PD1 immunotherapy in advanced melanoma.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
G. Prado Vázquez, L. Trilla Fuertes, A. Zapater Moros, E. López Camacho: Full/Part-time employment: biomedica Molecular Medicine. A. Gámez Pozo, J.A. Fresno Vara, E. Espinosa: Shareholder/Stockholder/Stock options: biomedica Molecular Medicine. All other authors have declared no conflicts of interest.
Introduction (ID 27)
- Lillian L. Siu (Toronto, Ontario, Canada)
Conclusions (ID 59)
- Christophe Massard (Villejuif, CEDEX, France)
- Christophe Massard (Villejuif, CEDEX, France)
18O - CC-90011 in patients (Pts) with advanced solid tumors (STs) and relapsed/refractory non-Hodgkin lymphoma (R/R NHL): Updated results of a phase I study (ID 168)
- Antoine Hollebecque (Villejuif, France)
- Antoine Hollebecque (Villejuif, France)
- Johann S. De Bono (London, United Kingdom)
- Stefania Salvagni (Bologna, Italy)
- Ruth Plummer (Newcastle-upon-Tyne, Tyne and Wear, United Kingdom)
- Patricia Niccoli (Marseille, France)
- Jaume Capdevila (Barcelona, Spain)
- Giuseppe Curigliano (Milan, Italy)
- Victor Moreno (Madrid, Spain)
- Filippo De Braud (Milan, Italy)
- Marta López-Brea (Santander, Spain)
- Patricia Martin-Romano (Villejuif, France)
- Eric Baudin (Villejuif, CEDEX, France)
- Marina Arias (Summit, NJ, United States of America)
- Juan De Alvaro (Summit, NJ, United States of America)
- Josep Parra-Palau (Summit, NJ, United States of America)
- Tania Sánchez-Pérez (Summit, NJ, United States of America)
- Ida Aronchik (Summit, NJ, United States of America)
- Ellen Filvaroff (Summit, NJ, United States of America)
- Manisha Lamba (Summit, NJ, United States of America)
- Zariana Nikolova (Boudry, Switzerland)
Abstract
Background
CC-90011 is an oral, potent, selective, and reversible inhibitor of lysine-specific demethylase 1A. Prior results from the CC-900011-ST-001 study showed that CC-90011 was well tolerated and had promising preliminary antitumor activity in pts with advanced unresectable STs and R/R NHL. Here we present updated results with longer follow-up and additional pts.
Methods
Pts in this phase I dose escalation (part A) and expansion (part B) study received CC-90011 once/wk (QW) in 28-d cycles. Primary endpoints were safety, maximum tolerated dose, and/or recommended phase 2 dose (RP2D). Secondary endpoints included pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy.
Results
Of 66 pts enrolled (50 in part A; 16 in part B), all but 1 pt had STs; 40 pts had neuroendocrine neoplasms (NENs). The primary objective of part A was met with an RP2D of 60 mg QW established. As of 13 Sept 2019, 6 pts remained on treatment. The primary reason for discontinuation was progressive disease (part A, 76%; part B, 63%). Thrombocytopenia was the most common treatment-related adverse event (AE; 47%) and the only serious AE reported in >1 pt in either part of the study; it was an on-target event that was reversible and easily managed. AEs led to discontinuation in 6% of pts in part A and 0 pts in part B; 1 pt in part B died of infection unrelated to CC-90011. Clinical benefit rate was 20% (95% CI, 10.0-33.7) in part A. One pt with NHL achieved a complete response (CR) and is ongoing in cycle 27 as of 13 Dec 2019; 3 pts had stable disease (SD) ≥20 cycles. Exposure increased proportional to dose. Negligible accumulation of exposure was observed with repeat dosing, and the terminal half-life was ∼60 h. Decreased levels of circulating neuroendocrine peptides and peripheral blood PD biomarkers indicated target engagement by CC-90011.
Conclusion
Results from this updated analysis show a consistent, well-tolerated safety profile and favorable PK and PD characteristics for CC-90011. Promising antitumor activity was observed in pts with advanced unresectable malignancies, including a durable CR in R/R NHL and prolonged SD in NENs. These data support further investigation of CC-90011.
Clinical trial identification
NCT02875223; EudraCT 2015-005243-13.
Editorial acknowledgement
Scarlett Geunes-Boyer, PhD from Bio Connections, LLC.
Legal entity responsible for the study
Bristol-Myers Squibb.
Funding
Bristol-Myers Squibb.
Disclosure
A. Hollebecque: Honoraria (self), Honoraria (institution), Travel/Accommodation/Expenses: Amgen; Honoraria (self), Honoraria (institution): Eisai; Honoraria (self), Honoraria (institution), Travel/Accommodation/Expenses: Servier; Advisory/Consultancy, Travel/Accommodation/Expenses: Astra-Zeneca; Advisory/Consultancy: Incyte; Advisory/Consultancy: Debiopharm; Travel/Accommodation/Expenses: Lilly; Travel/Accommodation/Expenses: Medimmune. J.S. de Bono: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sierra Oncology; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Daiichi; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Astra-Zeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Astellas; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bayer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech/Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Genmab; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: GSK; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Janssen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Serono; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Menarini Silicon Biosystems; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Orion; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Taiho; Research grant/Funding (institution): Cellcentric; Research grant/Funding (institution): Celgene, a Bristol-Myers Squibb Company; Research grant/Funding (institution): Menarini. R. Plummer: Advisory/Consultancy: Pierre Faber; Advisory/Consultancy: Genmab; Advisory/Consultancy: Bayer; Advisory/Consultancy: Octimet; Advisory/Consultancy, Licensing/Royalties: Clovis Oncology; Advisory/Consultancy: Novartis; Advisory/Consultancy: Karus Therapeutics; Advisory/Consultancy: Biosceptre; Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy: Cybrexa; Advisory/Consultancy: Sanofi A; Honoraria (self): Ellipses; Research grant/Funding (self): Astra-Zeneca; Travel/Accommodation/Expenses: MSD. J. Capdevila: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Ipsen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Advanced Accelerator Applications; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Eisai; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Astra-Zeneca; Advisory/Consultancy: Sanofi; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Celgene, a Bristol-Myers Squibb Company. G. Curigliano: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Honoraria (self), Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Honoraria (self): Novartis; Honoraria (self): Seagen; Advisory/Consultancy: BMS. V. Moreno: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: BMS; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Regeneron; Speaker Bureau/Expert testimony: Bayer/Loxo. F. De Braud: Advisory/Consultancy: Tiziana Life Sciences; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Celgene, A Bristol-Myers Squibb Company; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Servier; Advisory/Consultancy: Pharm Research Associated; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy, Speaker Bureau/Expert testimony: Ignyta; Advisory/Consultancy, Speaker Bureau/Expert testimony: Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy: Octimet Oncology; Advisory/Consultancy: Incyte; Advisory/Consultancy: Teofarma; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: EMD Serono; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bayer; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Nektar; Research grant/Funding (institution): Loxo Oncology; Research grant/Funding (institution): Tesaro; Speaker Bureau/Expert testimony: Astra-Zeneca; Speaker Bureau/Expert testimony: Gentili; Speaker Bureau/Expert testimony: Fondazione Menarini; Speaker Bureau/Expert testimony: MSD; Speaker Bureau/Expert testimony: Noema S.R.L.; Speaker Bureau/Expert testimony: ACCMED; Speaker Bureau/Expert testimony: Dephaforum S.r.l.; Speaker Bureau/Expert testimony: Nadirex; Speaker Bureau/Expert testimony: Biotechspert Ltd.; Speaker Bureau/Expert testimony: PriME Oncology. P. Martin-Romano: Research grant/Funding (institution), Non-remunerated activity/ies: Astra-Zeneca; Research grant/Funding (institution), Non-remunerated activity/ies: BMS; Research grant/Funding (institution), Non-remunerated activity/ies: Boehringer Ingelheim; Research grant/Funding (institution): Janssen Cilag; Research grant/Funding (institution), Non-remunerated activity/ies: Merck; Research grant/Funding (institution): Novartis; Research grant/Funding (institution), Non-remunerated activity/ies: Pfizer; Research grant/Funding (institution), Non-remunerated activity/ies: Roche; Research grant/Funding (institution): Sanofi; Non-remunerated activity/ies: Bayer; Non-remunerated activity/ies: Johnson & Johnson; Non-remunerated activity/ies: Lilly; Non-remunerated activity/ies: Medimmune; Non-remunerated activity/ies: NH TherAGuiX. J. Parra-Palau: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene, a Bristol-Myers Squibb Company. T. Sánchez-Pérez: Full/Part-time employment: Celgene, A Bristol-Myers Squibb Company. I. Aronchik: Shareholder/Stockholder/Stock options, Full/Part-time employment: BMS. E. Filvaroff: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment: BMS; Shareholder/Stockholder/Stock options: Amgen; Shareholder/Stockholder/Stock options: Gilead; Shareholder/Stockholder/Stock options: Genentech/Roche. M. Lamba: Shareholder/Stockholder/Stock options, Full/Part-time employment: BMS; Licensing/Royalties: Pfizer. Z. Nikolova: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene, A Bristol-Myers Squibb Company. All other authors have declared no conflicts of interest.
40P - The exosomes transfer the acquired resistance of MCF-7 breast cancer cells to rapamycin and tamoxifen (ID 173)
- Alexander M. Scherbakov (Moscow, Russian Federation)
- Alexander M. Scherbakov (Moscow, Russian Federation)
- Yuri Shchegolev (Moscow, Russian Federation)
- Danila Sorokin (Moscow, Russian Federation)
- Mikhail Krasil’nikov (Moscow, Russian Federation)
Abstract
Background
Resistance to targeted therapy is one of the important problems in oncology. The main purpose of the work was to study the exosomes involvement in the progression of the resistance of breast cancer cells.
Methods
MCF-7 breast cancer cell line was obtained from the ATCC collection. The cells-derived exosomes were isolated by ultracentrifugation and thoroughly characterised. Protein expression was measured by immunoblotting. To measure AP1 activity gene-reporter assay was used.
Results
The rapamycin-resistant MCF-7 cells were developed under long-term treatment of the cells with the increasing doses of rapamycin. The selected cells named as MCF-7/Rap were characterized with the resistance to rapamycin, and at the same time - the partial resistance to antiestrogen tamoxifen. We have shown that the treatment of the parent MCF-7 cells with exosomes from the resistant MCF-7/Rap cells within 14 days lead to the cross resistance of the MCF-7 cells to rapamycin and tamoxifen. The MCF-7/Rap cells and the cells with the exosome-induced resistance were characterized with the increased expression of mTOR-interacting Raptor protein, activation of Akt and transcriptional factor AP-1.
Conclusion
The results obtained demonstrate the important role of Akt/mTOR signaling in the development of exosome-induced cancer cell resistance to growth signal-targeting anti-tumor drugs.
Legal entity responsible for the study
The authors.
Funding
RSF (19-15-00245, resistance studies) and RFBR (18-29-09017, exosome characterization).
Disclosure
All authors have declared no conflicts of interest.
Conclusions (ID 22)
- Lee M. Ellis (Houston, TX, United States of America)
- Lee M. Ellis (Houston, TX, United States of America)
Introduction (ID 54)
- Patricia Lorusso (New Haven, MI, United States of America)
- Patricia Lorusso (New Haven, MI, United States of America)
Q&A (ID 259)
34P - Pharmacogenomics of docetaxel response in prostate cancer: A precision medicine initiative (ID 162)
- Abhinav Grover (Irvine, United States of America)
- Abhinav Grover (Irvine, United States of America)
- Sheldon Greenfield (Irvine, CA, United States of America)
- Sherrie Kaplan (Irvine, United States of America)
- Robert Stevenson (Irvine, United States of America)
- Edward Uchio (Irvine, United States of America)
Abstract
Background
Docetaxel therapy is approved for castration-resistant metastatic prostate cancer. However, it is unknown whether docetaxel should be added to the treatment regimen after patients become resistant to androgen deprivation therapy or only once they develop metastasis. Therefore, the aim of the study was to identify demographic, clinical and genetic predictors of docetaxel response which would help optimize both its use and timing for initiation.
Methods
A total of 209 prostate cancer patients were analyzed for factors predicting GRID (genome resource information database) gene expression scores for docetaxel response (score = 1-100) using linear regression. Factors included in the analysis were age, race, stress, comorbidity measured by TIBI-CaP (Total Illness Burden Index–Carcinoma Prostate), androgen receptor signaling and tumor proliferation signaling gene signatures, PSA (prostate specific antigen) levels, and Gleason grade.
Results
African American men had significantly lower docetaxel sensitivity compared to Whites based on GRID gene signatures. In a regression analysis, however, only comorbidity (β = -0.93, p=0.05), increasing androgen receptor signaling (β = 0.60, p <0.001) and tumor proliferation signaling gene signatures (β = 0.39, p <0.001) were significant predictors of genetics of docetaxel response independent of race. Additionally, TIBI-CaP was significantly correlated with tumor proliferation. The model explained 42% variance in the genetics of docetaxel response.
Conclusion
Optimization of docetaxel therapy use in prostate cancer should take into account patient’s comorbidity, androgen receptor signaling and tumor proliferation signaling gene signatures. Comorbidity may be exerting its effect on docetaxel response by increasing the chances of proliferation of the prostate tumor cells. The pharmacogenomics of docetaxel response could aid precision medicine initiatives by improving survival rates in prostate cancer patients.
Legal entity responsible for the study
The authors.
Funding
California Initiative to Advance Precision Medicine.
Disclosure
All authors have declared no conflicts of interest.
Introduction (ID 17)
- Lee M. Ellis (Houston, TX, United States of America)
- Lee M. Ellis (Houston, TX, United States of America)
Proteosomal degradation as a mechanism to tackle difficult targets (ID 49)
- Raj Chopra (London, United Kingdom)