Proffered Paper session: New and early developments with new concepts Proffered Paper session

Session DOI (ID 223)

Lecture Time
11:00 - 11:00
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
11:00 - 12:15
Opening and welcome + Honorary award Keynote lecture Educational session

Welcome address – TAT 2019 Scientific Committee (ID 2)

Lecture Time
08:50 - 08:55
Speakers
  • A. Adjei
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
25.02.2019
Time
08:45 - 09:30
Authors
  • A. Adjei
Methodological issues in IO Educational session

Biomarkers & endpoints (ID 35)

Lecture Time
15:35 - 15:55
Speakers
  • A. Marabelle
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
15:30 - 17:30
Authors
  • A. Marabelle
Workshop: How to choose a drug to study, biomarkers, etc. Workshop

Drug development: Lessons from success (ID 100)

Lecture Time
12:55 - 13:05
Speakers
  • G. Schwartz
Location
Room 341, Palais des Congrès, Paris, France
Date
26.02.2019
Time
12:45 - 13:30
Authors
  • G. Schwartz
Cocktail and Poster viewing Poster Display session

12P - Targeting HIF1α/AP1 in hypoxia by novel 7-amino-6-halogeno-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides (ID 140)

Presentation Number
12P
Lecture Time
18:25 - 18:25
Speakers
  • A. Scherbakov
Location
Hall Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
18:00 - 18:45
Authors
  • A. Scherbakov
  • G. Buravchenko
  • L. Dezhenkova
  • A. Shchekotikhin

Abstract

Background

HIF-1α and AP1 play important roles in hypoxia and activate anti-apoptotic pathways in tumor cells. No dual HIF-1α/AP1 inhibitors currently exist, so targeting these transcriptional factors is promising way to modulate hypoxia signaling in cancer cells. Aim of the study was obtaining and biological evaluation of hypoxia-selective 7-amino-6-halogen-substituted derivatives starting from 6,7-dihalogeno-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides.

Methods

A series of 7-amino-6-halogeno-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides was synthesized. Cancer cell lines were purchased from ATCC. The cytotoxic activity of compounds was evaluated in normoxia (21%O2) and hypoxia (1%O2). The cytotoxicity was assessed by MTT test (72 h growth with compounds). HIF-1α and AP1 activity was assessed by reporter analysis.

Results

Synthesis of 7-amino-6-halogen- substituted derivatives starting from 6,7-dihalogeno-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides was carried out. A series was characterized by good solubility in water. Antiproliferative activity was evaluated in vitro on a panel of cancer cell lines including multidrug resistance variants. Novel synthesized compounds demonstrated higher hypoxia selectivity and cytotoxicity compared with tirapazamine. Some of the 7-amino-6-halogeno derivatives were 10-20-fold more potent than the reference drug. Selected 7-amino-6-halogeno derivatives LCTA-2425 and LCTA-2711 inhibited breast cancer cells growth in hypoxia at concentrations lower than 0.6 µM. Compounds LCTA-2711 and LCTA-2425 showed inhibitory effects on HIF-1α- and AP1-dependent luciferase activity, when tirapazamine revealed no potency to block these factors in MCF-7 breast cancer cells under hypoxic conditions.

Conclusions

A series of 7-amino-6-halogeno-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides were more potent than reference drug tirapazamine in all tested cell lines and demonstrated high selectivity in hypoxia. Selected 7-amino-6-halogeno derivatives showed dual inhibitory activity against HIF-1α and AP1 factors, regulating anti-apoptotic pathways in hypoxia. RFBR grants 18-53-34005 (chemistry), 18-015-00422 (biology).

Legal entity responsible for the study

Alexander M. Scherbakov.

Funding

Russian Foundation for Basic Research, Grants 18-53-34005 (Chemistry) and 18-015-00422 (Biology).

Disclosure

All authors have declared no conflicts of interest.

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Opening and welcome + Honorary award Keynote lecture Educational session

Session DOI (ID 214)

Lecture Time
08:45 - 08:45
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
25.02.2019
Time
08:45 - 09:30
Immune checkpoint combinations: How to marry rationally Educational session

Preclinical models to assess timing of combination regimens (ID 26)

Lecture Time
09:45 - 10:05
Speakers
  • S. Khleif
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
09:00 - 10:30
Authors
  • S. Khleif
Take home messages and close Educational session

Take home messages and close (ID 59)

Lecture Time
15:00 - 15:15
Speakers
  • C. Massard
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
27.02.2019
Time
15:00 - 15:15
Authors
  • C. Massard
Selected Poster Presentation Poster Display session

9P - Safety profile and therapeutic efficacy of one cycle of [177Lu]prostate-specific membrane antigen (PSMA) in end stage metastatic castration-resistant prostate cancer patients with low performance status (ID 79)

Presentation Number
9P
Lecture Time
17:40 - 17:45
Speakers
  • M. Gupta
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
17:30 - 18:00
Authors
  • M. Gupta
  • P. Choudhury
  • S. Rawal
  • H. Goel
  • V. Talwar
  • K. Dutta
  • A. Singh

Abstract

Background

Prostate cancer patients with distant metastasis have poor prognosis and develop resistance to all standard drugs at various time intervals. Therapeutic options which can alleviate symptoms and prolong survival are required for these patients. [177Lu]prostate-specific membrane antigen ([177Lu]PSMA) is a novel drug based on a theranostic concept. Here, we have presented the safety and efficacy profile of one cycle of [177Lu]PSMA in metastatic castration-resistant prostate cancer (mCRPC) patients who have exhausted all standard therapeutic options.

Methods

Twenty two patients treated with at least first line anti-androgens and docetaxel were treated with one cycle of [177Lu]PSMA therapy on a compassionate basis. Haemoglobin, total leukocyte counts, platelets and serum creatinine for toxicity profile while prostate specific antigen (PSA), Eastern Cooperative Oncology Group (ECOG) performance status, visual analogue scale (VAS) and analgesic quantification scale (AQS) for therapeutic efficacy were recorded pre and 8 weeks post therapy. Wilcoxon signed-rank and ANOVA tests were used for statistical analysis.

Results

Partial response (PR), stable disease (SD) and progressive disease (PD) for PSA were seen in 5 (22.7%), 13 (59.1%) and 4 (18.2%) patients, respectively, treated with mean 6.88GBq dose of [177Lu]PSMA. 8/22 (36.4%) patients showed ≥ 30% drop in PSA. Grade 3 haemoglobin toxicity was seen in 5/22 (22.7%) patients. No patient developed grade 4 haemoglobin toxicity. No patients had grade 3 or 4 leukocytopenia or thrombocytopenia. Wilcoxon signed-rank test showed statistically significant (p < 0.05) difference in pre- and post-treatment ECOG, VAS, AQS scores while it was not significant for PSA (P > 0.05). ANOVA test showed a statistically significant difference in mean doses of [177Lu]PSMA used in the three PSA response groups while the difference was non-significant for other variables.

Conclusions

We conclude that [177Lu]PSMA therapy delivers adequate pain palliation in all end-stage mCRPC patients and it has a potential to become an effective therapeutic option in properly selected patients.

Legal entity responsible for the study

Manoj Gupta.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Cocktail and Poster viewing Poster Display session

27P - Detection of genomic alterations in breast cancer (BC) patients with paired plasma and tumour specimens (ID 131)

Presentation Number
27P
Lecture Time
18:25 - 18:25
Speakers
  • Y. Yap
Location
Hall Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
18:00 - 18:45
Authors
  • Y. Yap
  • D. Ho
  • R. Ng
  • C. Chan
  • A. Lee
  • I. Tan
  • S. Ng

Abstract

Background

There is increasing interest in the use of circulating tumour DNA (ctDNA) to identify targetable genomic alterations for therapy selection. However, the feasibility of next generation sequencing on ctDNA in BC patients with varying disease burden merits further investigation.

Methods

The cohort of 35 BC patients included 30 metastatic cases with paired primary and metastatic specimens in addition to plasma taken prior to commencement of a new line of palliative systemic therapy (all subtypes), + 5 patients (3 stage III, 2 stage II) about to commence neoadjuvant systemic therapy. DNA from tumour, buffy coat and plasma was sequenced on a 77-gene capture panel customised for BC. Matched tumour/normal samples were processed to discover somatic alterations using a standard GATK pipeline. Plasma samples were processed using unique molecular identifiers to identify potential alterations at low frequency.

Results

Among the entire cohort, 74% (26/35) of patients had mutation(s) in at least 1 gene detected from ctDNA: 60% (3/5) for the neoadjuvant cases, 77% (23/30) for the metastatic cases. The most frequently mutated genes from ctDNA analysis were TP53 (17/35; 49%) and PIK3CA (8/35; 23%), with HER2, HER3, JAK2, NF1, MAGI3 and TSC2 mutations observed in 2 patients each (6%). There was no obvious correlation between detection of ctDNA mutation and disease burden, serum CA-15.3 tumour marker or circulating tumour cell levels using a microfluidic platform. Out of 35 patients, 21(60.0%) had ≥1 concordant mutation via both ctDNA and tumour genotyping. Concordance between the plasma and primary and/or metastatic lesions was observed for 59% (39/66) of the mutations detected in ctDNA. Among the metastatic cases, 14/37(38%) of the concordant mutations were shared between the plasma, primary and metastatic specimens, while 5(14%) were shared between the plasma and the primary only, and 18/37(49%) shared between the plasma and metastatic lesions only.

Conclusions

Detection of genomic alterations from ctDNA is feasible in BC patients, but concordance of mutations in ctDNA is better with the metastatic than the primary lesion. This is likely due to suboptimal quality of DNA from archived tissue, and spatial, temporal heterogeneity.

Legal entity responsible for the study

National Cancer Centre Singapore and Genome Institute of Singapore.

Funding

SingHealth Foundation.

Disclosure

Y.S. Yap: Personal financial interests, honoraria for consultancy and talks, travel support: AstraZeneca, Eisai, Lilly, Novartis, Pfizer, Roche. All other authors have declared no conflicts of interest.

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Learning from haemato-oncology trials Educational session

Introduction (ID 17)

Lecture Time
15:45 - 15:50
Speakers
  • V. Ribrag
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
25.02.2019
Time
15:45 - 17:15
Authors
  • V. Ribrag
KRAS Educational session

Inhibiting K-ras in the clinic: The saga continues (ID 50)

Lecture Time
12:05 - 12:25
Speakers
  • A. Adjei
Session Name
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
27.02.2019
Time
11:00 - 12:30
Authors
  • A. Adjei