Functional diagnostics as a new concept for the improvement of personalized targeted therapy
2022
Authors:
Dragoj, MiodragDinić, Jelena
Podolski-Renić, Ana
Jovanović Stojanov, Sofija
Jovanović, Mirna
Stepanović, Ana
Ercegovac, Maja
Marić, Dragana
Pešić, Milica
Document Type:
Conference object (Published version)
,
© 2022 by the STRATAGEM COST Action
Metadata
Show full item recordAbstract:
Although advances in sequencing technology and target identification enabled the implementation of a
personalized therapy approach, unfortunately, only 3-9% of cancer patients who receive the targeted
therapy show an adequate response. On the other side, there are exceptional responders to targeted
therapy among cancer patients without common genetic alterations. Therefore, current patient
classifications relying only on sequencing are not sufficient to determine optimal treatment. Our
intention is to start in the opposite direction to conventional diagnostics by performing pharmacological
screening on patient-derived cancer cells ex vivo because testing of multiple drugs is not possible in
clinical trials. An incomplete understanding of how tumour genotype reflects on tumour phenotype
limits the efficacy of DNA and mRNA sequencing for personalized therapy. Functional diagnostics using
patient-derived cancer cells is recently implicated to overcome this limitation and it is clinically available
for haematological malignancies. We plan to perform the immunofluorescence-based drug-screening
assay to determine non-small cell lung carcinoma (NSCLC) patients’ cancer cells’ response to targeted
therapeutics, particularly tyrosine kinase inhibitors (TKIs) within the time frame necessary to influence
patient care. The usage of the functional diagnostics approach should be an addition to clinical trials and
complement DNA and mRNA sequencing.
In contrast to similar research efforts [1], we will shorten the cultivation of NSCLC patient-derived
cells to 1-2 weeks because we intend to test drugs on a mixture of cancer and stromal cells (fibroblasts).
It is well-known that the sensitivity of cancer cells depends on their interaction with the
microenvironment including neighbouring cells. In addition, we will examine the changes in the
expression level of ATP Binding Cassette transporters (ABCB1, ABCC1, and ABCG2) in both cancer
and stromal cells that may occur during TKIs and chemotherapy treatment. In such way, we will gain
knowledge about (i) which TKI or chemotherapeutic induces multidrug-resistant (MDR) phenotype in
our NSCLC patients’ cohort, (ii) whether the induction of MDR depends on the ratio between cancer
and stromal cells, (iii) whether the induction of MDR is prevalent in cancer cells, and (iv) whether MDR
induction depends on individual patient’s characteristics (comparison with Whole Exome Sequencing
results).
Keywords:
Functional diagnostics; personalized; targeted therapy; NSCLC; MDRFunding / projects:
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200168 (University of Belgrade, Faculty of Chemistry) (RS-MESTD-inst-2020-200168)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200026 (University of Belgrade, Institute of Chemistry, Technology and Metallurgy - IChTM) (RS-MESTD-inst-2020-200026)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200007 (University of Belgrade, Institute for Biological Research 'Siniša Stanković') (RS-MESTD-inst-2020-200007)
In:
- Abstract Book: STRATAGEM’s 5th Annual Meeting: New Diagnostic and Therapeutic Tools against Multidrug Resistant Tumours; 2022 Jun 29 - Jul 1; Coimbra, Portugal. STRATAGEM COST Action; 2022. p. 94.