Draft:Functional drug sensitivity testing

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Functional drug sensitivity testing (f-DST) is an in-vitro diagnostic test method in functional precision medicine..[1] developed to personalize the choice among cytotoxic drugs and drug combinations for patients with an indication for systemic chemotherapy in specific cancer types. [2] [3] [4] f-DST is performed by various in-vitro diagnostic methods which have in common to quantify reactions of individual patient-derived cancer tissue when exposed to cytotoxic drugs. As substrate, testing methods initially require live cancer tissue from an individual patient (metastases or primary tumor).

Bioptic samples containing live cancer tissue are processed to obtain the required type, histologic organization and number of carcinomatous cells, ie. isolated cells, cell clusters, organoids or tumoroids of defined sizes.

The processed cancer specimen, cell or organized cell aggregates, are then cultured in stem cell media to increase in number and expand into a sufficient number of testable cancer cell aggregates as required, depending on the used test model. [5]

After defined time periods of culture, often between 3 and 7 days, cell or organized cell aggregates are counted and transferred to drug screening arrays, where they are exposed to defined concentrations of the cytotoxic drugs or drug combinations in question.

Measurement methods and statistical analyses usually focus on cell/cell aggregate behaviour in vitro under exposure to the test drugs after defined periods of time.

In vitro reactions of those patient-derived cancer cell or cell aggregates following exposure to standardized cytotoxic drug concentrations over a specified time are then calculated based on positive and negative controls and/or to calibration curves obtained from reference populations. [6]

Background and Rationale

Cytotoxic sytemic chemotherapies are generally considered effective across larger patient populations on average [7], but are known to come with different individual and side effect profiles. Therapeutic choices are currently based on the individual patient's overall medical situation and potential side effect tolerability. However, individual responses to systemic chemotherapy is known to vary due to differences in tumor biology, genetic makeup, and other factors. [8] This variability can affect the therapeutic risk/benefit ratio.

Methodology and Laboratory Procedures

f-DST methodology comprises three basic steps: Pre-analytical processing of cancerous tissue samples, cultivation of the testable cellular product (ie. tumoroids, organoids, cell clusters, single cells) and subsequent exposition to the clinically most important cytotoxic agents (5-FU, oxaliplatin, irinotecan, individually or in combinations (CAPOX, FOLFOX, FOLFIRI, FOLFOXIRI), as well as to other cytotoxic substances [9], [10]

Clinical Application

f-DST provides information on an individual patient's tumoroids / organoids / cell cluster / cell vulnerabilities towards cytotoxic chemotherapies in vitro[11]

Limitations and Future Directions

f-DST requires repeat, fresh cancerous tissue biopsy procedures, which is not standard of care in the routine diagnostic workup of solid tumor patients in all stages of the disease [12].

If organoids or tumoroids are cultured for the purpose of fDST, results start being available from between 14 to 21 days after the bioptic procedure [13].

Like other functional testing methods (e.g. antibiograms), none of the current f-DST methods claims to fully replicate the intricate interactions of tumor tissue within a patient's body. However, information obtained by f-DST is being clinically investigated regarding relevant endpoints such as progression free survival [14].

f-DST is an emerging in vitro diagnostic tool. It has the potential to shift the current average cytotoxic drug efficacy / side effects risk balance of classic systemic chemotherapies for which no individual biomarkers exist.

References

  1. ^ Letai, A (Jan 10, 2021). "Functional precision oncology: Testing tumors with drugs to identify vulnerabilities and novel combinations". Cancer Cell. 40 (1): 26–35. doi:10.1016/j.ccell.2021.12.004. PMC 8752507. PMID 34951956.
  2. ^ Letai, A (2022). "Functional Precision Medicine: Putting Drugs on Patient Cancer Cells and Seeing What Happens". Cancer Discov. 12 (2): 290–292. doi:10.1158/2159-8290.CD-21-1498. PMC 8852353. PMID 35140175.
  3. ^ Sakshaug, Christoffer (2023). "Systematic revew: predictive value of organoids in colorectal cancer". Scientific Reports. 13 (1): 18124. Bibcode:2023NatSR..1318124S. doi:10.1038/s41598-023-45297-8. PMC 10593775. PMID 37872318.
  4. ^ Bouquerel, Charlotte (2023). "Bridging the gap between tumor-on-chip and clinics: a systematic review of 15 years of studies". The Royal Society of Chemistry. 23 (18): 3906–3935. doi:10.1039/d3lc00531c. PMID 37592893. S2CID 260969209.
  5. ^ Napoli, Giulia C.; Figg, William D.; Chau, Cindy H. (2022-07-08). "Functional Drug Screening in the Era of Precision Medicine". Frontiers in Medicine. 9. doi:10.3389/fmed.2022.912641. ISSN 2296-858X. PMC 9307928. PMID 35879922.
  6. ^ Jensen, Lars Henrik; Jakobsen, Anders Kristian Moeller; Havelund, Birgitte Mayland; Abildgaard, Cecilie; Vagn-Hansen, Chris; Dam, Claus; Lindebjerg, Jan; Canto, Luisa M; Rogatto, Silvia Regina; Rafaelsen, Soeren Rafael; Hansen, Torben (2021-05-20). "Functional precision medicine in colorectal cancer based on patient-derived tumoroids and in-vitro sensitivity drug testing". Journal of Clinical Oncology. 39 (15_suppl): e15567. doi:10.1200/JCO.2021.39.15_suppl.e15567. ISSN 0732-183X.
  7. ^ Cervantes, A (2023). "Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up". Annals of Oncology. 34 (1): 10–34. doi:10.1016/j.annonc.2022.10.003. PMID 36307056. S2CID 253137096.
  8. ^ Cremolini, C (2020). "Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer". Lancet Oncol. 21 (4): 497–507. doi:10.1016/S1470-2045(19)30862-9. hdl:2434/771383. PMID 32164906. S2CID 212690097.
  9. ^ Jensen, Lars Henrik (2023). "Precision medicine applied to metastatic colorectal cancer using tumor-derived organoids and in-vitro sensitivity testing". Journal of Experimental & Clinical Cancer Research. 42 (115): 115. doi:10.1186/s13046-023-02683-4. PMC 10161587. PMID 37143108.
  10. ^ Kondo, Jumpei (March 28, 2011). "Retaining cell–cell contact enables preparation and culture of spheroids composed of pure primary cancer cells from colorectal cancer". PNAS. 108 (15): 6235–6240. Bibcode:2011PNAS..108.6235K. doi:10.1073/pnas.1015938108. PMC 3076886. PMID 21444794.
  11. ^ Ulukaya, Engin (19 Jun 2021). "Tumor Chemosensitivity Assays Are Helpful for Personalized Cytotoxic Treatments in Cancer Patients". Medicina (Kaunas). 57 (6): 636. doi:10.3390/medicina57060636. PMC 8234301. PMID 34205407.
  12. ^ Kmeid, Michel; Brar, Rupinder; Sullivan, Luz; Arslan, Mustafa Erdem; Shrestha, Neharika; Lee, Edward C.; Chen, Anne; Jennings, Timothy A.; Lee, Hwajeong (2023-02-01). "Diagnostic yield and repeat biopsies in rectal and nonrectal colorectal adenocarcinoma: Are we hedging on rectal biopsies?". Academic Pathology. 10 (1): 100063. doi:10.1016/j.acpath.2022.100063. ISSN 2374-2895. PMC 10031322. PMID 36970329.
  13. ^ Napoli, Giulia C.; Figg, William D.; Chau, Cindy H. (2022-07-08). "Functional Drug Screening in the Era of Precision Medicine". Frontiers in Medicine. 9: 912641. doi:10.3389/fmed.2022.912641. ISSN 2296-858X. PMC 9307928. PMID 35879922.
  14. ^ "Search of: functional drug sensitivity test | Recruiting, Not yet recruiting Studies - List Results - ClinicalTrials.gov". classic.clinicaltrials.gov. Retrieved 2024-03-19.
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