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Drug testing of patient derived tumor organoids identified high sensitivity to the EGFR targeting drug lapatinib, consistent with HER2 amplification. Remarkably, this patient achieved a complete remission with a combination of EGFR inhibitor trastuzumab and pertuzumab followed by a personalized vaccine, and is currently disease free. This study indicates the potential of functional testing of patient derived tumor cells to identify effective therapies for cancers with poor outcome.
Organoids are self-organizing, expanding 3D cultures derived from stem cells. Using tissue derived from patients, these miniaturized models recapitulate various aspects of patient physiology and disease phenotypes, including genetic profiles and drug sensitivities
The accompanying news story discusses how big Pharma, in this case Roche, saw the light and realizedthat patient derived tumor model, which share both somatic and germlinegenetics of a given patient would be a useful model system for both drug development and precision medicine. It is only a matte of time until others catch on.
A roadblock to acceptance of ex vivo drug testing using patient derived tumor cells is demonstration of clinical utility, specifically prospective evidence of patient response. The attached review by Wensink et al. summarizes findings from 17 different studies and concludes that ‘The currently available results offer an optimistic perspective that individualized tumour response testing using PDO shave clinical validity as a predictive biomarker for cancer patients. The pooled sensitivity and specificity for discriminating patients with a clinical response through PDO-based screening were 0.81 (95% CI 0.69–0.89) and 0.74 (95%CI 0.64–0.82), respectively.'
Precision medicine is starting to incorporate functional assays to evaluate anticancer agents on patient-isolated tissues or cells to select for the most effective. Among these new technologies, dynamic BH3 profiling (DBP) has emerged and extensively been used to predict treatment efficacy in different types of cancer. DBP uses synthetic BH3 peptides to measure early apoptotic events (‘priming’) and anticipate therapy-induced cell death leading to tumor elimination. This predictive functional assay presents multiple advantages but a critical limitation: the cell number requirement, that limits drug screening on patient samples, especially in solid tumors.
The story begins decades ago with a man named Stanley Korsmeyer, who led the molecular oncology program at Dana-Farber from 1998 until his death in 2005. He discovered that B-cell cancers like CLL over-produced a protein called BCL-2, and interfered with apoptosis, or programmed cell death. But how that went from an interesting discovery to a game-changing cancer drug is a story of persistence and momentum, and it’s the first episode of season two of Unraveled
The 4th Precision Oncology Symposium of the Comprehensive Cancer Center Zurich will bring together international leaders in the field of functional precision medicine including oncologists, cancer researchers and data experts to discuss latest developments and future directions. Click the button below to register today!
Patients with non-Hodgkin’s lymphomas (NHLs) often relapse after frontline treatment, and interpatient heterogeneity make personalized combination treatment difficult. Goh et al. have developed a hybrid experimental-analytic method that they call quadratic phenotypic optimization platform, or QPOP, to identify personalized drug combination therapies using ex vivo patient samples to improve patient outcomes. In a prospective cohort, physicians were able to alter treatment according to drug combinations identified using QPOP after 6 days to achieve complete responses in 5 of 17 patients with NHL. This is a promising step for providing new hope for patients who have relapsed NHL and provides a foundation for further clinical trials.
A follow up to our October Seminar
The BCL2 inhibitor venetoclax has revolutionized the treatment of AML patients not benefiting from intensive chemotherapy. Nevertheless, treatment failure remains a challenge, and predictive markers are needed, particularly for R/R AML. Although, the ex vivo drug sensitivity testing has been used by several research groups, very few prospective trials have analyzed the correlation of drug sensitivity testing results to treatment outcome
VenEx is a prospective Phase 2 trial aiming to evaluate if ex vivo drug sensitivity testing could be used to identify AML patients who benefit from venetoclax + azacitidine therapy. This interim analysis of 39 first trial participants demonstrated that the experimental conditions significantly influenced predictive accuracy. Blast-specific venetoclax sensitivity measured in conditioned medium most accurately correlated with treatment outcomes; 88% of sensitive participants achieved treatment response. Median survival was significantly longer for ex vivo sensitive participants. This analysis illustrates the feasibility of integrating drug-response profiling into clinical practice and demonstrates excellent predictivity. The second stage of the trial is on-going to validate these results.
The American Society of Hematology welcomes SFPM President Dr. Tony Letai, Dr. Philipp Staber, & Dr. Caroline Heckman to discuss "Functional Precision Hematology" at their October 11 webinar.