HHS Public Access

Author manuscript
Cancer Cell. Author manuscript; available in PMC 2023 October 14.
Author Manuscript

Published in final edited form as:

Cancer Cell. 2022 December 12; 40(12): 1448–1453. doi:10.1016/j.ccell.2022.09.017.

A Path to Translation: How 3D Patient Tumor Avatars Enable

Next-Generation Precision Oncology
Shree Bose1, Margarida Barroso2, Milan G. Chheda3, Hans Clevers4,5, Elena Elez6,
Salma Kaochar7, Scott E. Kopetz8, Xiao-Nan Li9,10, Funda Meric-Bernstam11, Clifford
A. Meyer12,13,14, Haiwei Mou15, Kristen M. Naegle16, Martin F. Pera17, Zinaida Perova18,
Katerina A. Politi19, Benjamin J. Raphael20, Paul Robson21,22,23, Rosalie C. Sears24, Josep
Author Manuscript

Tabernero6, David A. Tuveson25, Alana L. Welm26, Bryan E. Welm27, Christopher D.

Willey28, Jeffrey H. Chuang21,22,23,*, Konstantin Salnikow29,*, Xiling Shen30,*
1.Departmentof Pharmacology and Cancer Biology, Duke University School of Medicine, Durham,
NC 27708, USA
2.Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, 12208,
USA
3.Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110 USA
4.Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and
University Medical Center, Uppsalalaan 8, Utrecht, 3584 CT, Netherlands
5.Roche Pharma, Research and Early Development (pRED) of F. Hoffmann-La Roche Ltd, Basel,
Switzerland
Author Manuscript

6.Vall
d’Hebron Hospital Campus and Institute of Oncology, International Oncology Bureau-
Quiron, University of Vic-Central University of Catalonia, Barcelona, 08035 Spain
7.Department of Medicine, Dan L Duncan Comprehensive Cancer Center, Baylor College of
Medicine, Houston, TX, 77030, USA
8.The University of Texas MD Anderson Cancer Center, Houston, TX, 77030 USA
9.Ann& Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School
of Medicine, Chicago, IL, 60611 USA
10.Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, 60611
USA
Author Manuscript

11.Departmentof Investigational Cancer Therapeutics, The University of Texas MD Anderson

Cancer Center, Houston, TX, 77030 USA
12.Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, 02215 USA
13.Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215
USA

*
Correspondence: [email protected] (Jeffrey H. Chuang), [email protected] (Xiling Shen).
Declarations of Interest
M.S., B.J.R., P.R., X.L., B.E.W., A.L.W. do not report any conflicts.
 Bose et al. Page 2

14.Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, 02215
Author Manuscript

USA
15.The Wistar Institute, Philadelphia, PA 19104 USA
16.University
of Virginia, Department of Biomedical Engineering and the Center for Public Health
Genomics, Charlottesville, VA, 22903, USA
17.The Jackson Laboratory, Bar Harbor, ME 04660, USA
18.EuropeanMolecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome
Campus, Hinxton, Cambridge, CB10 1SD, UK
19.Departmentsof Pathology and Internal Medicine (Medical Oncology), Yale School of Medicine
and Yale Cancer Center, New Haven, CT 06510, USA
20.Department of Computer Science, Princeton University, Princeton, NJ, 08540, USA
Author Manuscript

21.The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032 USA
22.Departmentof Genetics and Genome Sciences, University of Connecticut School of Medicine,
Farmington, CT, 06032 USA
23.Institute for Systems Genomics, University of Connecticut, Farmington, CT, 06032 USA
24.Department
of Medical and Molecular Genetics, Oregon Health & Science University, Portland,
OR 97201, USA
25.LustgartenFoundation Pancreatic Cancer Research Laboratory at Cold Spring Harbor
Laboratory, Cold Spring Harbor, NY 11724 USA
26.Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake
Author Manuscript

City, UT, 84112, USA

27.Department of Surgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT,
84112, USA
28.Department
of Radiation Oncology, The University of Alabama at Birmingham, Birmingham,
AL, 35294 USA
29.Division of Cancer Biology, National Cancer Institute, NIH, Rockville, MD 20850, USA
30.Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90024, USA

Abstract
3D patient tumor avatars (3D-PTAs) hold promise for next-generation precision medicine. Here
Author Manuscript

we describe the benefits and challenges of 3D-PTA technologies and necessary future steps to
realize their potential for clinical decision-making. 3D-PTAs require standardization criteria and
prospective trials to establish clinical benefits. Innovative trial designs combining omics and 3D-
PTA readouts may lead to more accurate clinical predictors, and an integrated platform combining
diagnostic and therapeutic development will accelerate new treatments for patients with refractory
disease.

Cancer Cell. Author manuscript; available in PMC 2023 October 14.

 Bose et al. Page 3

Precision medicine, as defined in modern oncology, has focused on the development of

Author Manuscript

therapies that target specific genetic alterations in cancer. Imatinib (Gleevec) for leukemias
with BCL-ABL mutations, Trastuzumab (Herceptin) for HER2-overexpressing cancers, and
others were promising early demonstrations of this vision. In 2006, the National Institutes
of Health (NIH) launched The Cancer Genome Atlas, a landmark cancer genomics program
that sequenced over 11,000 primary cancer samples. The precision medicine approach was
simple: sequence a patient’s tumor, identify driver mutations, and administer therapies to
target those mutations. With tumors dependent on the targeted oncogenes, early successes
bolstered collaborations between pharmaceutical companies and academic research for rapid
drug development.

With only a small subset of targetable mutations, a minority of cancer patients are thought
to actually benefit from genome-guided therapies1. Given our growing appreciation for other
drivers of neoplastic behaviors (metabolic, phenotypic, epigenetic, and microenvironmental)
Author Manuscript

and tumor evolution during treatment, the need for an approach that integrates more biology
into therapeutic decision-making is evident. With the support of key national funding
entities, including the NIH, biorepositories of patient-derived models have been developed;
however, their application in precision medicine has been largely dependent on their ability
to adequately recapitulate the clinical response of patient tumors in a laboratory setting. The
advantages and limitations of each of these models have been extensively reviewed (Figure
1A).

While a mainstay of cancer research over several decades, 2D cell cultures are not
ideal models of tumors, often representing only the most rapid-growing cells in a plate
rather than the diversity of the neoplastic growth2. Patient-derived xenograft (PDX)
models, or murine models of cancer using patient tumor tissue engrafted into immune-
Author Manuscript

compromised mice, have been a critical component of translational modeling. While

valuable in their ability to capture genetic diversity and other features of patient tumor
physiology, serial PDX modeling through patient treatment and tumor evolution is often not
feasible due to substantial cost and time requirements of PDXs. Additionally, the murine
stromal tumor microenvironment (TME) and need for immune reconstitution in PDXs
makes immuno-oncology studies challenging, thus obligating the further development of
other preclinical models. Ex vivo explants, or cultures of whole tissue, capture the 3D
architecture and cellular organization of tumor samples, although the amount of required
tissue, low throughput, and difficulty in reproducibility limit their scalability for clinical
implementation.

In recent years, 3D-PTAs have rapidly emerged as a new model system to explore tumor
Author Manuscript

behaviors. These models, ranging from patient-derived organoids (PDOs) to microscale

models like organotypic tumor spheroids (PDOTs), 3D bioprinting, organoids-on-a-chip, and
micro-organospheres (MOS), can model cellular behaviors while capturing characteristics
true to the source tissue3–7. Several landmark studies demonstrated that PDOs could
predict patient tumor response to chemotherapy and radiation8–10. While PDX models
often require 6–8 months for development and expansion, PDOs can reduce this time to
weeks with higher throughput11. More recently, microscale 3D-PTA technologies leveraging

Cancer Cell. Author manuscript; available in PMC 2023 October 14.

 Bose et al. Page 4

microfabrication or microfluidics have achieved substantially faster establishment and

Author Manuscript

higher throughput.

Although promising, these efforts on 3D-PTAs will require standardization and concerted
buy-in from regulatory bodies, clinicians, researchers, and patients to bridge the gap between
bench and bedside, and key recommendations to achieve this goal are discussed here (Figure
1B).

Standardizing Practices and Protocols

While the expertise of select groups has demonstrated the viability of 3D-PTAs as tools
for modeling cancer, the variability in their creation remains a hurdle for reproducibility
and clinical adoption. The skill of the operator remains an important driver of success in
establishing both PDOs and ex vivo explants, with the most successful biobanking efforts
Author Manuscript

reporting establishment rates of 70–95% which can decrease in other settings8, 12. Defining
and standardizing precise methods to validate whether 3D-PTAs adequately capture the
significant inter- and intratumoral heterogeneity of source tissue will also be crucial to
deriving insights from this data.

Defining the extracellular matrix (ECM) scaffolds, media and cocktails of growth factors
best suited for different types of 3D-PTAs has been a key effort of many groups, including
the NCI-sponsored Patient-Derived Models of Cancer (PDMC) Consortium; however,
standard precise culture methods remain elusive and different cancer types will likely
require more specific tailoring. Derived from mouse sarcoma, Matrigel tends to have
batch-to-batch variability, while the effects of alternative scaffolds such as synthetic gel
on 3D-PTA establishment and drug response have not been well characterized. Variations
in adding common factors, whether fetal bovine serum (FBS) or antibiotics (penicillin,
Author Manuscript

streptomycin, primocin, etc.) into culture media with supraphysiologic glucose is relatively
commonplace. However, the consequent metabolic effects of these combinations are poorly
understood but likely of importance. In 3D-PTAs, the need to harvest tissue from donors
can also lead to variations in the time and amount of tissue without perfusion, leading
to warm vs. cold-ischemic changes that are difficult to characterize. Finally, the post-
processing of these tissues – whether using clean-up procedures to remove necrotic tissue,
applying specialized media to isolate different immune, stromal, or tumoral components,
or mycoplasma surveillance methodologies – adds another layer of variability between
studies. As individual labs often optimize growth factor concentrations based on their
own experience, results are sometimes hard to compare across publications because of the
variabilities discussed above12–14. As standardized protocols are developed for 3D-PTAs,
these practices must be codified and shared across research groups.
Author Manuscript

Following the establishment and experimentation of 3D-PTAs, quantifying results with

validated software pipelines is essential to establishing their reproducibility and functional
readouts as well15. Further standardization and automation of these processes—handling
of source material, culture conditions, validated reproduction of source characteristics, and
measurements of endpoints like proliferation and survival—will enhance reproducibility.
Together with independent replication studies, these factors will form an important

Cancer Cell. Author manuscript; available in PMC 2023 October 14.

 Bose et al. Page 5

foundation for using 3D-PTAs as companion support tools in research and clinical decision-
Author Manuscript

making.

Standardizing Patient Data Collection

As the number and complexity of tumoral samples collected for large scale 3D-PTA
biobanks expand, the clinical factors that are captured should be well-documented to
ensure that analytical approaches can draw meaningful conclusions. Specifically, clinical
parameters of race and ethnicity, body-mass index, and socio-economic factors have come to
be recognized as crucial to overall outcomes for patients but are not routinely available for
large-scale biobanks. Other metadata to include in studies should include sex, age, sample
collection dates, sample processing, cancer types and full history (initial presentation,
metastases, stage/grade, treatment lines), family history, and tobacco exposure. While
these parameters have been reported in studies when relevant to the outcomes of interest,
Author Manuscript

capturing that heterogeneity as a dimension of 3D-PTA libraries will enable a more holistic
understanding of the predictive capabilities of these functional models.

These requirements for patient data collection need to be established and supported by
overseeing bodies–including the NIH, institutions, and journals which publish these studies.
Key to achieving this will be to adopt common regulatory frameworks for data exchange
and access at a global scale. Building on the example of the PDX Minimal Information
Standard (PDX-MI), standards around the clinical information, patient metadata collection,
and patient informed consent for 3D-PTAs studies should be developed in the coming
years, particularly as we find ourselves at the beginning of this confluence of big data and
biorepository development.
Author Manuscript

Innovating Clinical Trial Designs

While is a well-established framework for genomic testing in accredited laboratories exists,
the path for validation of 3D-PTAs for clinical decision-making is yet to be established. As
with genome-guided therapy, 3D-PTA-guided therapies must undergo rigorous prospective
clinical trials to demonstrate clinical benefits for clinical adoption, regulatory approval, and
eventually, payer reimbursements. Currently, many clinical trials are seeking to assess the
potential of 3D-PTAs to advance the management of patients with various tumor types
in different settings. These clinical studies include observational (non-interventional) “co-
clinical trials” aiming to evaluate the feasibility of deriving 3D-PTA-based assays from
tissue biopsies in a turnaround time compatible with clinical workflows, as demonstrated
by a recent clinical study using the MOS technology6. As a next step, the potential of
this platforms for predicting response rates and progression-free survival must be shown
Author Manuscript

with either a prospective validation trial, where clinicians are informed of the 3D-PTA
assay prediction when choosing between equipoised approved or investigational drugs,
or in the setting of a randomized pilot study with an uninformed arm where 3D-PTA
is not performed, and patients are managed as per available best practice. Quantitative
measurements of immune, stromal, and tumor cell types over time could help define
the temporal fidelity of 3D-PTAs and their utility in modeling tumor heterogeneity and
evolution. Ultimately, results from these validation studies will buoy the efforts of early

Cancer Cell. Author manuscript; available in PMC 2023 October 14.

 Bose et al. Page 6

adopters, while providing the basis for further clinical utility trials. These studies, with larger
Author Manuscript

cohort sizes, randomized arms, and clinically-meaningful endpoints of progression-free

survival or overall survival, will be the foundation for adoption by the broader community
and National Comprehensive Cancer Network (NCCN) guidelines.

3D-PTA guided prospective trials can further leverage window-of-opportunity trial designs,
which test experimental drugs before standard-of-care (SOC) regimens. Upon biopsy, 3D-
PTA assays can be performed to test both experimental drugs and equipoised SOC regimens.
During the short period of time prior to SOC treatment, typically ~10–20 days, patients
can be treated with experimental therapies and evaluated by a second biopsy and imaging
(e.g., PET) or other assays (e.g., circulating tumor DNA) to assess drug on-target activity
and early response as well as adaptive resistance programs. These window-of-opportunity
trials allow 3D-PTA readouts to be correlated with experimental drug responses while
guiding SOC decision-making as well, thus providing valuable insights into the biological
Author Manuscript

effects and mechanisms of action that accelerate development of new drugs and combination
regimens. Further, 3D-PTAs may be used to evaluate the sensitivity of non-targeted
chemotherapy-based regimens that lack molecular markers to guide patient care and offer
additional treatment options to therapy-refractory patients.

Furthermore, 3D-PTAs can serve as valuable tools to guide patient selection and optimize
enrollment for specific experimental therapies. While current clinical trials often provide
limited benefit for a majority of enrollees, 3D-PTAs can be used to predict patient
response and stratify treatment cohorts accordingly, similar to genome-guided umbrella trial
designs. Such precision clinical trials could increase the benefits that enrollees derive from
experimental therapies—enhancing patient survival, improving quality-of-life, encouraging
accruement, reducing trial risk, and utilizing precious clinical resources more efficiently.
Author Manuscript

Lastly, where current trials often fail to capture racial and socioeconomic diversity
adequately, 3D-PTA may provide a more personalized platform to address such disparities
and benefit minority and disadvantaged populations by treating them as unique individuals
rather than relying on statistics from unrepresentative populations.

Omics- vs. 3D-PTA-Guided Therapeutics

Advances in genome- and function-based assays have occurred largely in parallel; however,
the burgeoning confluence of the two has already begun to yield important insights –
recapitulating associations with genetic mutations and targeted therapeutic sensitivities and
pinpointing mutations which may be of interest for future investigation. A major question
remains yet unanswered: can patient response be more accurately predicted by one or both
Author Manuscript

in combination?

As a patient can only receive one treatment at a time, 3D-PTAs offer the opportunity to
perform high-throughput screen with library of drugs in parallel and drug combinations,
while also guiding lower-throughput in vivo studies. When combined with molecular
profiling, these functional models may provide much-needed training datasets to improve
the performance of current omics-based predictors. Ultimately, as expanding clinical

Cancer Cell. Author manuscript; available in PMC 2023 October 14.

 Bose et al. Page 7

trials and growing repositories offer increasing statistical power, the combination of the
Author Manuscript

molecular-guided and functional 3D-PTA guided therapies will likely outperform either
alone while also providing the most predictive capabilities for future precision medicine
efforts (Figure 1C). In this functional precision medicine approach, larger volumes of
biopsied tissue can be both molecularly profiled and used to establish PTAs for functional
drug response assays. A computational predictor trained using both omics and PTA readouts
will be used to predict patient response, which can be gauged against patient endpoints.
This integrative approach may be particularly impactful in evaluating clinical approaches to
overcome resistance to specific therapies.

In addition to the clinical impact of these predictive computational models, the development
of analytical pipelines which can integrate the metabolic, (phospho)proteomic, immune,
morphological, and genetic data gathered from libraries of 3D-PTAs may also yield insights
into previously unknown associations. Thus, further work on using 3D-PTAs and omics
Author Manuscript

analyses in combination with well-defined computational pipelines to analyze them may

better define the precise features of 3D-PTAs that contribute to their predictive value15.
To this end, federal funding agencies should leverage relevant consortia such as NCI
PDMC, PDXnet, TEC, and CSBC to systematically compare omics-based biomarkers and
3D-PTA drug responses to quantify the predictive power of each alone and in combination.
European academic research infrastructures dedicated to the development of preclinical
models (i.e., INFRAFRONTIER, EuroPDX) are currently assessing the clinical value of
pan-cancer 3D-PTA platforms for advancing precision oncology efforts, both at an academic
and translational level. The European initiative, HCA-Organoid, is leveraging single-cell
technologies in PDOs to enable therapeutic advances. Ultimately, an integrated approach
will create synergy between these global scientific communities, improving omics and
3D-PTA models as the repositories continue to evolve with growing clinical specimens and
Author Manuscript

data.

Integrating Diagnostic and Therapeutic Development

3D-PTAs pose the unique opportunity to perform de novo testing of new, experimental drugs
or off-label drugs that lack existing clinical data, an impossible undertaking for clinical
-omics predictors that require patient response data to be trained on. The importance of
this capability for both drug testing and development is manifold. For one, next-generation
precision medicine must be able to identify new treatments for patients who are refractory
to existing SOC. As new drugs are increasingly more specific and targeting smaller patient
populations, pharmaceutical companies are facing the challenge of finding and accruing
the right patients for clinical trials, thus increasing the cost, time, and risk of new drug
Author Manuscript

development. 3D-PTAs offer an opportunity to bring new drugs to market in a safe,

expedited manner with preliminary clinical trials carried out using patient surrogates that
can increase the likelihood of downstream success. Similarly, 3D-PTAs offer a unique
opportunity to expand drug repurposing strategies that may provide solutions to unmet
clinical needs.

The next generation of precision medicine must incorporate the heterogeneity of the patient
population into every step of the diagnosis-treatment cascade. While current diagnostic

Cancer Cell. Author manuscript; available in PMC 2023 October 14.

 Bose et al. Page 8

and therapeutic developments are largely siloed, 3D-PTA functional precision medicine can
Author Manuscript

serve as an integrated workflow to enhance cancer care and expedite clinical development of
new drugs (Figure 1D). The clinical biomarkers captured by the omics profiling combined
with the functional readout from the 3D-PTA can guide the patient to either SOC or new
therapeutics in clinical trials. Compared to conventional clinical trial accrual, functional
precision medicine may represent a more effective approach in selecting appropriate
therapies, thereby improving quality and length of life while reducing clinical resource
wastage and unnecessary toxicity from ineffective therapies.

Furthermore, the 3D-PTAs from the diagnostic assays can be further passaged and
preserved to form 3D-PTA biobanks with diverse clinical response data that capture
patient heterogeneity. These are already becoming invaluable resources for pre-clinical
drug and biomarker discovery as well as AI-based learning algorithms, which can then
aid development of both new diagnostics and therapies. Finally, aggregating the data
Author Manuscript

derived from these studies and making it accessible to the broader scientific community via
resources like PDCM Finder (www.cancermodels.org) will maximize the utility of 3D-PTAs
for precision oncology.

Conclusion
3D-PTAs hold tremendous promise for next-generation precision medicine, with support
from initiatives around the globe. However, for these technologies to fulfill their envisioned
goals as clinical decision-making tools, further work is necessary to build on what the
scientific communities have accomplished so far. The remaining challenges to incorporation
of 3D-PTAs include standardization of techniques and patient metadata collection, analytical
tools, and the development of new clinical trial designs, all of which require a concerted
Author Manuscript

community-wide effort guided by the best practices and standards proposed here. Physician
scientists, or clinical key opinion leaders, from around the world will set the standards to
develop and ensure 3D-PTAs can be incorporated into clinical practice and drive patient care
that is truly personalized.

Acknowledgements
We thank the NCI 3D Workshop, Patient-Derived Model of Cancer (PDMC) Program, and PDXNet for constructive
discussions, recommendations, and purposeful efforts to advance the practice of precision oncology.

S.B., M.B., H.M., Z.P., C.A.M., K.M.N., M.F.P., R.C.S. and J.H.C. have no competing interests to declare.
S.E.K. is an advisor to Xilis, Inc. F.M.B. declares consulting/advisory fees from AbbVie, Aduro BioTech Inc.,
Alkermes, AstraZeneca, Daiichi Sankyo Co. Ltd., DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche
Ltd., Genentech Inc., Harbinger Health, IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life
Science, Lengo Therapeutics, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Protai Bio Ltd, Samsung
Author Manuscript

Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks, Black Diamond,
Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology,
Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Sanofi, Silverback
Therapeutics, Spectrum Pharmaceuticals, Zentalis; sponsored research to her institution from Aileron Therapeutics,
Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics
Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant
Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co.
and honoraria for a speaking engagement from Chugai Biopharmaceuticals. S.K. is a consultant for FGH BioTech
and has received research funding from FGH BioTech and Systems Oncology. K.A.P. is co-inventor on a patent
for EGFRT790M mutation testing issued, licensed, and with royalties paid from Molecular Diagnostics/Memorial
Sloan Kettering Cancer Center. She reports research funding to the institution from AstraZeneca; Roche/Genentech,

Cancer Cell. Author manuscript; available in PMC 2023 October 14.

 Bose et al. Page 9

Boehringer Ingelheim, and D2G Oncology; and consulting for AstraZeneca and Jannssen. M.G.C. reports grants
from NeoImmuneTech, as well as other support from Orbus Therapeutics, Incyte, Merck, and UpToDate outside
Author Manuscript

the submitted work; in addition, M.G.C. has a patent for Zika virus strains for the treatment of glioblastoma
pending. E.E.’s full disclosures are given here: www.bit.ly/3xuWMer. J.T. reports personal financial interest in form
of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi
Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena
Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona
Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology,
Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics and TheraMyc. Stocks:
Oniria Therapeutics and also educational collaboration with Imedex/HMP, Medscape Education, MJH Life
Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). D.A.T. is a member
of the Scientific Advisory Board and receives stock options from Leap Therapeutics, Surface Oncology, Cygnal
Therapeutics, Mestag Therapeutics and Xilis, Inc. outside the submitted work. D.A.T. is scientific co-founder of
Mestag Therapeutics. D.A.T. has received research grant support from Fibrogen, Mestag, and ONO Therapeutics.
D.A.T. receives grant funding from the Lustgarten Foundation, the NIH, and the Thompson Foundation. None of
this work is related to the publication. No other disclosures were reported. C.D.W. is a part-time consultant for
LifeNet Health and receives grant funding from AACR-Novocure and Varian Medical Systems. X.S. and H.C. are
cofounders of Xilis, Inc. and inventors on patents related to organoid research and micro-organospheres. X.S. is
CEO of Xilis, Inc. H.C.’s full disclosure is given here: www.uu.nl/staff/JCClevers/Additionalfunctions.
Author Manuscript

References
1. Marquart J, Chen EY & Prasad V. Estimation of the percentage of US patients with cancer who
benefit from genome-driven oncology. JAMA oncology 4, 1093–1098 (2018). [PubMed: 29710180]
2. Letai A Functional precision cancer medicine—moving beyond pure genomics. Nature medicine 23,
1028 (2017).
3. Jenkins RW et al. Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor SpheroidsEx
Vivo Profiling of Immune Checkpoint Blockade. Cancer discovery 8, 196–215 (2018). [PubMed:
29101162]
4. Sato T et al. Long-term expansion of epithelial organoids from human colon, adenoma,
adenocarcinoma, and Barrett’s epithelium. Gastroenterology 141, 1762–1772 (2011). [PubMed:
21889923]
5. Park SE, Georgescu A & Huh D Organoids-on-a-chip. Science 364, 960–965 (2019). [PubMed:
31171693]
Author Manuscript

6. Ding S et al. Patient-derived micro-organospheres enable clinical precision oncology. Cell Stem Cell
29, 905–917. e906 (2022).
7. Langer EM et al. Modeling tumor phenotypes in vitro with three-dimensional bioprinting. Cell
reports 26, 608–623. e606 (2019).
8. Bose S, Clevers H & Shen X Promises and challenges of organoid-guided precision medicine. Med
2, 1011–1026 (2021). [PubMed: 34617071]
9. Vlachogiannis G et al. Patient-derived organoids model treatment response of metastatic
gastrointestinal cancers. Science 359, 920–926 (2018). [PubMed: 29472484]
10. Ganesh K et al. A rectal cancer organoid platform to study individual responses to chemoradiation.
Nature medicine 25, 1607–1614 (2019).
11. Hidalgo M et al. Patient-derived xenograft models: an emerging platform for translational cancer
research. Cancer discovery 4, 998–1013 (2014). [PubMed: 25185190]
12. van Tienderen GS et al. Hepatobiliary tumor organoids for personalized medicine: a multicenter
view on establishment, limitations, and future directions. Cancer cell 40, 226–230 (2022).
Author Manuscript

[PubMed: 35148815]
13. Xie AW & Murphy WL Engineered biomaterials to mitigate growth factor cost in cell
biomanufacturing. Current Opinion in Biomedical Engineering 10, 1–10 (2019).
14. Veninga V. & Voest EE Tumor organoids: opportunities and challenges to guide precision
medicine. Cancer Cell 39, 1190–1201 (2021). [PubMed: 34416168]
15. Kong J et al. Network-based machine learning in colorectal and bladder organoid models predicts
anti-cancer drug efficacy in patients. Nature communications 11, 1–13 (2020).

Cancer Cell. Author manuscript; available in PMC 2023 October 14.

 Bose et al. Page 10
Author Manuscript
Author Manuscript
Author Manuscript

Figure 1:
Author Manuscript

3D-PTAs as Precision Oncology Tools. (A) Comparison of advantages and disadvantages of

current patient tumor models. (B) 3D-PTAs face key barriers to for widespread adoption in
clinical decision-making. (C) Paradigm to understand benefits of combinatorial or omics- vs.
3D-PTA-guided drug selection. (D) 3D-PTAs can be evaluated as functional complements to
molecular tumor characterization in clinical trials and as a powerful tool for understanding
tumor biology for further drug development.

Cancer Cell. Author manuscript; available in PMC 2023 October 14.