The preliminary study of patient-derived metastatic brain tumors in a highly mimetic ex vivo spheroid-based physiological model for clinical precision therapeutics

doi:10.21203/rs.3.rs-4350341/v1

Download PDF

Article

The preliminary study of patient-derived metastatic brain tumors in a highly mimetic ex vivo spheroid-based physiological model for clinical precision therapeutics

https://doi.org/10.21203/rs.3.rs-4350341/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Metastatic brain tumors present a formidable challenge in clinical oncology due to their heterogeneity and limited treatment options. This study aimed to introduce and assess the patient-derived tumor spheroid (PDTS) system as an innovative approach for precision drug testing in metastatic brain tumors. By replicating the brain tumor microenvironment ex vivo, our goal is to improve the selection of effective anticancer drugs tailored to individual patients. Using decellularized extracellular matrix (dECM) from adipose tissues, the PDTS system generated tumor spheroids from surgical tissue samples for drug testing. In preliminary data, 17 patients met the criteria for final analysis, which showed an overall 57% accuracy, with improvements to 73% accuracy when patients receiving certain treatments were excluded. This ex vivo model offers real-time results within three weeks, simultaneous testing of multiple drugs, and the ability to culture and store tumor cells for reproducibility. Despite limitations, such as the inability to simulate the blood‒brain barrier or study immune system interactions, the PDTS represents a valuable tool for precision medicine in metastatic brain tumors. Further research and refinement may lead to its integration into clinical practice, ultimately improving outcomes for patients with metastatic brain tumors.

Biological sciences/Biotechnology

Biological sciences/Cancer

Health sciences/Diseases

Health sciences/Medical research

Health sciences/Neurology

Health sciences/Oncology

metastatic brain tumor

patient-derived organoid

patient-derived

micro-organosphere

precision oncology

Metastatic brain tumors are more common than primary brain tumors (tumors that originate in the brain). They can arise from various types of cancer, with the most common primary sites being the lungs, breast, colon, kidney, and skin (melanoma). Patients with metastatic brain tumors have short survival times. The multimodal management of brain metastases has focused primarily on the utilization of neurosurgical techniques, with varying combinations of whole-brain radiation therapy (WBRT) or stereotactic radiosurgical procedures (XRT). Currently, systemic medical treatment for metastatic brain tumors is at the forefront of patient-specific management¹. Precision treatment using preclinical models or whole-genome sequencing has been proposed. However, even with targeted molecular genetics, only a small proportion of patients benefit from DNA sequencing-guided drug selection². The ability of patient-derived tumor xenografts (PDTXs) to predict therapeutic response is largely limited by logistical factors³. This poses a major challenge for precise cancer treatment. Cancer cell-derived organoids and spheroids are considered desirable systems for predicting the response to treatment^4–6. In a prior study conducted by Shie et al.⁷, this model was demonstrated to be effective as an ex vivo predictive model for personalized lung cancer therapy, achieving remarkably high accuracy (85%), sensitivity (86.7%), and specificity (80%).

In this study, we utilized the same novel patient-derived tumor spheroid (PDTS) system to replicate the brain tumor microenvironment, aiming to explore the connection between patient clinical outcomes and findings from ex vivo patient-specific cancer spheroids. Unlike previous studies^4–6, bovine adipose tissues were subjected to decellularization through a series of chemical and enzymatic treatments, ensuring the complete removal of cellular remnants, nuclei, and DNA. Despite this thorough process, the adipose-derived extracellular matrix (adipose-dECM) retains essential structural and cellular elements, such as collagen (COL) and glycosaminoglycans (GAGs), from both native and decellularized adipose tissue. Given that the human brain is comprised of approximately 60% fat, this preservation highlights the potential of adipose-dECM to serve as a supportive scaffold for brain tumor cells. Additionally, its ease of acquisition and fabrication make it a practical choice. Moreover, this system offers an appropriate environment for coculturing brain tumor cells.

The main goal of this study was to conduct a coclinical trial of 17 patients with a total of 18 metastatic brain tumors. Their treatment responses were recorded and compared to the results from ex vivo patient-specific cancer spheroids. Furthermore, the accuracy, sensitivity, and specificity of brain tumor spheroids were validated. The basis for developing a novel ex vivo cancer spheroid model for metastatic brain tumors was provided and implemented to predict different combinations of clinical drugs.

In our study, participants underwent craniotomy resection and were processed to create patient-derived tumor spheroid models following the approved Institutional Review Board(IRB) protocol of China Medical University Hospital in Taichung City, Taiwan (CMUH110-REC2-183). The date of first registration is on 29/09/2020. All experiments strictly adhered to CMUH guidelines and regulations, and informed consent was obtained from all participants or their legal guardians. Between December 2021 and September 2023, we enrolled a total of 62 patients. We excluded 33 patients who did not receive any systemic anticancer therapy, 3 patients without confirmed clinical outcomes from imaging studies, and 9 patients with primary CNS tumors based on pathologic reports. Thus, 17 patients and a total of 18 metastatic brain tumors were included in the final analysis (see Fig. 1). Patient data are presented in Table 1.

Table 1

Testing anticancer drugs and their functions and indications
Testing anticancer drugs	Functions and indications
Osimertinib	Osimertinib is prescribed for the treatment of NSCLC that has progressed to a locally advanced or metastatic stage. It is specifically effective when the cancer cells exhibit certain genetic mutations, such as the T790M mutation in the EGFR gene or activating mutations in EGFR.
Afatinib	Afatinib is a medication utilized in the treatment of NSCLC. It falls under the category of tyrosine kinase inhibitors, a class of medications that target specific enzymes involved in cancer cell growth and progression.
Eribulin	Eribulin, a fully synthetic macrocyclic ketone analog, acts as a potent mitotic inhibitor through a distinct mechanism. It is approved for treating locally advanced or metastatic breast cancer and unresectable liposarcoma in adults.
Docetaxel	Docetaxel is a chemotherapy drug that works by disrupting microtubule function, halting cell division. It is employed in the treatment of various cancers, including breast, head and neck, stomach, prostate, and NSCLC.
Dabrafenib-Trametinib	The dabrafenib-trametinib combination is recommended for individuals with advanced cancers harboring the BRAF V600E mutation, such as NSCLC, melanoma, and anaplastic thyroid cancer. Dabrafenib and trametinib target distinct growth-promoting signals activated by this mutation: dabrafenib inhibits BRAF protein signals, and trametinib inhibits MEK protein signals.
UFT capsules	UFT is a combination drugs of tegafur and uracil in a molecular ratio of 1:4. Tegafur is gradually converted to 5-FU, and 5-FU is phosphorylated into active metabolites. According to a pooled analysis of Japanese phase II trials of UFT-alone treatment for advanced unresectable solid tumors originating from a variety of organs including the lung, stomach, colorectal, and breast, the objective response rate was 25.1%.
TS-1	TS-1 is a combination medication comprising tegafur, gimeracil, and oteracil potassium. Tegafur serves as a prodrug of 5-FU, an oral fluoropyrimidine, intended as an alternative to infusional 5-FU therapy. TS-1-based chemotherapy, including TS-1 combined with cisplatin, represents a rational first-line treatment for unresectable advanced gastric cancer. Additionally, TS-1-based chemotherapy demonstrates effectiveness in treating colorectal cancer, achieving a response rate of 41%.
Cyclophosphamide	Cyclophosphamide is a versatile medication utilized in chemotherapy and immunosuppression. Primarily administered alongside other chemotherapy agents, it plays a crucial role in treating various cancers including lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer, small cell lung cancer, neuroblastoma, and sarcoma.
Vinorelbine	Vinorelbine is a chemotherapy drug employed in the treatment of various cancers, notably breast cancer and NSCLC. Its mechanism of action involves inhibiting mitosis by interacting with tubulin, thereby exhibiting antitumor activity
Cisplatin	Cisplatin acts via noncell cycle-specific cytotoxicity, which is achieved through the covalent binding of platinum to the purine bases guanine and adenine. Cisplatin is FDA approved for the treatment of advanced ovarian cancer, testicular cancer, and bladder carcinoma.
Carboplatin	Carboplatin functions by binding to and cross-linking DNA, thereby disrupting replication and inhibiting cancer cell growth. It is utilized in the treatment of various cancers, including ovarian, lung, head and neck, brain, triple-negative breast cancer, and neuroblastoma.
Gemcitabine	Gemcitabine is effective in treating several carcinomas. It is employed as a first-line treatment alone for pancreatic cancer and in conjunction with cisplatin for advanced bladder cancer and NSCLC. Additionally, it serves as a second-line treatment alongside carboplatin for ovarian cancer and with paclitaxel for metastatic or inoperable breast cancer. The mechanism of action of gemcitabine involves incorporating into DNA, inducing an irreparable error that halts further synthesis, ultimately leading to cell death.
Epirubicin	Epirubicin is the 4’ epimer of the anthracycline antibiotic doxorubicin and had been used alone or in combination with other cytotoxic agents in the treatment of a variety of malignancies. Epirubicin is primarily used against breast, ovarian cancer, gastric cancer, lung cancer and lymphomas.
Regorafenib	Regorafenib, an oral multikinase inhibitor created by Bayer, targets angiogenic, stromal, and oncogenic receptor tyrosine kinases. Its anti-angiogenic effects stem from dual inhibition of VEGFR2-Tie2 tyrosine kinases. Indications for Regorafenib encompass metastatic colorectal cancer, advanced gastrointestinal stromal tumors, and advanced HCC.
Abbreviations: NSCLC: non-small cell lung cancer; EGFR: epidermal growth factor receptor; MEK: Mitogen-activated protein kinase kinase; 5-FU: 5-Fluorouracil; FDA: U.S. Food and Drug Administration; DNA: Deoxyribonucleic acid; HCC: hepatocellular carcinoma

Among the 17 patients included in our study, metastatic brain tumors originated from various primary cancers, including lung cancer (6 patients), breast cancer (4 patients), and one patient each of gastric cancer, melanoma, esophageal cancer, hepatocellular carcinoma, cervical cancer, colon cancer, and nasopharyngeal cancer. Notably, patients No. 6 and No. 11 were the same individuals who underwent brain tumor surgery twice due to recurrent brain metastasis. Patient No. 3 modified their treatment plan in response to documented tumor progression during the study. The average age of our participants was 58.5 years, ranging from 37 to 76 years. The mean follow-up period was 7.86 months, ranging from 3 to 15 months.

According to our drug screening data, the overall sensitivity, specificity, and accuracy were 54.5%, 50%, and 57.8%, respectively. However, it is important to note the limitations of our model, as it does not incorporate the immune system, making it unsuitable for testing immunotherapy or cell therapy. Additionally, although we added an endothelial cell layer to the PDTS models, angiogenesis mechanisms and angiogenesis inhibitors were not investigated in this study. Patients who received the aforementioned systemic medical treatments were excluded from our analysis. With this refined selection, the accuracy of our test improved to 73.3% (11 out of 15), with a sensitivity of 75% (6 out of 8) and specificity of 71.4% (5 out of 7) (Fig. 2).

Patient no. 10

A 76-year-old female with no prior history of cancer received a new diagnosis of two sizable brain tumors located in the right frontal lobe and left occipital lobe and initially presented with left-sided weakness. Further evaluation through chest CT revealed multiple mass lesions in both lungs and right lower lung consolidation, raising a strong suspicion of lung cancer with brain metastasis (Fig. 3). The patient underwent a craniotomy for the removal of the right frontal brain tumor, and the pathological report confirmed its origin as metastatic adenocarcinoma of lung origin. Subsequently, no additional surgery was performed for the occipital brain tumor. Tissue from the frontal brain tumor was processed through the PDTS model, and the report, published three weeks later, provided valuable insights.

The presence of an EGFR mutation was also confirmed by a pathologist. Subsequently, the treatment plan was adjusted to include whole-brain radiation therapy (WBRT) and targeted therapy with osimertinib. In her PDTS model, osimertinib at a concentration of 1 µM demonstrated a relative cell viability of 70%, indicating a positive response (Fig. 4). Over the course of 10 months following the initiation of treatment, chest CT and brain MRI scans at 3 and 9 months consistently revealed significant shrinkage of the tumors. Remarkably, the clinical outcomes closely aligned with the predictions made by the PDTS model, highlighting the potential of the system to guide and optimize personalized cancer therapies (Fig. 5).

Various drug testing platforms are available for patient-specific tumor models, including in vitro 2D systems, 3D systems, organ-on-a-chip systems, and in vivo animal models. Each model has its own advantages and drawbacks⁸. Previous studies have extensively investigated the molecular mechanisms underlying tumor growth and dissemination through two-dimensional culture models. However, it has been repeatedly demonstrated that these models fail to accurately replicate the complexities of tumor expansion and the structural features of the tumor microenvironment. Consequently, these methods frequently yield inadequate predictions regarding drug responses⁹. Researchers are dedicated to developing alternative in vitro models for human cancers. In response to this challenge, traditional subcutaneous implants are no longer available because they cannot replicate the growth of organ tissues or the differences in responses to actual treatments¹⁰. Instead, human tumor xenografts, known as patient-derived xenografts (PDXs), are implanted into "in situ" organ sites of origin in mice^11–14. In vivo in situ cancer models offer a more accurate representation of tumor growth and metastasis. However, there are still challenges in assessing how changes in the microenvironment over time affect cancer cell behavior, and the organ microenvironment may not perfectly mimic that of humans. Moreover, these models necessitate a longer cultivation period, and thus, cannot provide timely information crucial for precise patient treatment, particularly in the context of metastatic brain tumors.

The PDTSs utilized in this study hold significant promise for advancing personalized cancer medicine. These 3D cultures, which are derived from a patient's own tumor tissue, better capture the heterogeneity and complexity of the original tumor than traditional 2D cell cultures. PDTSs not only serve as valuable tools for basic cancer research but also offer capabilities for drug screening and predicting treatment responses¹⁵. They boast several advantages over 2D systems, including greater physiological relevance, suitability for clinical tests, and support for high-throughput screening^4,6,16,17.

In our previous study¹⁸, we explored the potential of patient-derived organoids (PDOs) as a platform for precision treatment of malignant brain tumors. Our prospective clinical investigation demonstrated that PDOs derived from both primary and metastatic brain tumors could effectively guide treatment selection, thereby enhancing patient survival rates. However, the success rate of organoid culture remains at only 50%, with a culture time of approximately 2–3 weeks. Additionally, quantifying total cell numbers in PDOs presents challenges, making it difficult to accurately assess drug efficacy. These limitations hinder the clinical application of PDOs.

The PDTS model, resembling a 3D system, features a unique biomimetic environment that incorporates a brain tumor spheroid and a functional endothelial cell layer with good cell–cell interactions, mimicking the blood–brain barrier (BBB) in vivo. This allows for a more accurate simulation of drug delivery within the human vascular system. Additionally, the model facilitates comprehensive recreation of cellular interactions, including those between cells and the extracellular matrix (ECM), as well as variations in chemical and physical gradients within the cellular microenvironment. Importantly, it addresses the limitations of traditional 3D in vitro models, such as the absence of a functional vascular network for nutrient and gas transportation and the removal of toxic byproducts generated by cells. The PDTS model offers several advantages. It can provide drug test results to doctors within three weeks, enabling real-time decision-making. Moreover, our platform allows simultaneous detection of multiple drugs and quantitative testing of different drug concentrations, enhancing the accuracy of reports. Additionally, by culturing and storing tumor cells, our system ensures reproducibility and facilitates the retesting of other drugs, providing further clinical insights.

However, our model has certain limitations. Particularly for metastatic tumors, variations in growth and differentiation often result in differences across different organs of the human body. Furthermore, growth patterns and drug responses can significantly differ based on the unique microenvironment of each organ. Consequently, when using the same model, the predictive value of drug tests may vary between the brain and the organs of origin. Additionally, our PDTS model does not include a mechanism for studying angiogenesis, which prevents our testing of angiogenesis inhibitors such as bevacizumab. Moreover, our model does not incorporate the immune system, and the immune system is a vital component for evaluating the efficacy of immunotherapy, which is a commonly used treatment approach today. Another factor that could impact the accuracy of the PDTS model is the heterogeneity of clinical outcomes due to patients receiving multimodal management, including radiotherapy, targeted therapy, chemotherapy, immunotherapy, or cell therapy. In our study, two patients received cell therapy, one received hormone therapy, and one underwent oophorectomy for breast cancer, potentially influencing the outcomes of medical treatments and subsequently affecting the accuracy of testing. In this study, we employed a novel PDTS model to replicate the microenvironment of brain tumors, aiming to investigate the correlation between patient clinical outcomes and findings from ex vivo PDTSs. To achieve this goal, we utilized bovine adipose-derived extracellular matrix (dECM) as a supportive scaffold for brain tumor cells and cocultured a layer of endothelial cells to simulate the blood‒brain barrier (BBB) and for drug delivery. A coclinical trial involving 17 patients with a total of 18 metastatic brain tumors was conducted to validate the results obtained from the ex vivo PDTS models. The PDTS model demonstrated an accuracy rate of 73% for anticancer drug testing in metastatic brain tumors, with a specificity of 75% and a sensitivity of 71%. This model has the potential to become a standard in vitro model for clinical applications, as it can effectively simulate activities within a patient’s body that resemble the microenvironment and organ systems, including mechanical and physiological responses. Additionally, it offers a cost-effective and high-throughput approach, thereby contributing to advancements in cancer treatment. Given the frequently severe clinical condition of patients with brain metastases, it is crucial to note that recruiting participants for this study has been challenging. To advance this clinical study, a larger sample size and longer follow-up periods are needed.

Patients

This study included patients aged 18 years and older who underwent brain surgery for brain tumors. The exclusion criteria were as follows: (1) lack of informed consent; (2) confirmed primary brain tumor diagnosis; (3) absence of postoperative systemic anticancer drug treatment due to poor clinical condition; and (4) lack of imaging follow-up for clinical outcome evaluation. Tissue samples were collected during surgery; these samples included tumor specimens from the affected area and adjacent normal tissue for comparison. The samples were estimated to be 0.5 × 0.5 × 0.5 cm to 1.0 × 1.0 × 1.0 cm in size.

Materials and methods in the laboratory

After surgery, the tissue samples were isolated, and cells were obtained. These cells were expanded in culture (up to a maximum of P2 cell generation).

Decellularization of bovine adipose tissue

The decellularization procedure first involved removing nonspecific connective tissue from bovine adipose tissue. The adipose tissue was then sliced into 1 to 2 cm³ pieces, soaked in PBS solution, and stirred at room temperature for 3 hours. Subsequently, the tissue slices were treated with a 0.5% SDS solution in 1.5 M NaCl at 37°C for 24 hours. Following SDS treatment, the slices were incubated in isopropanol at room temperature for 48 hours, followed by treatment with 0.1% peracetic acid in 4% ethanol for 4 hours at room temperature. After washing, the decellularized tissues were freeze-dried for 48 hours and stored at -20°C. Later, 10 mg of AdECM was dissolved in 0.5 M acetic acid. Then, 1 mg of pepsin was added, and the mixture was incubated at 37°C for 2 days. The AdECM solution was neutralized to a pH of 7.4 and stored at 4°C for biological applications.

PDTS system

According to Shie's report, PDTS models offer an excellent 3D in vitro biomimetic platform for simulating hypoxic conditions and replicating native scenarios, thus enabling detailed investigations into drug responses. Each cell type was cultured in its respective medium, with medium changes occurring every 2 or 3 days. Before being embedded in AdECM, the cells were harvested using 0.25% trypsin in EDTA, followed by centrifugation at 1200 rpm for 10 minutes. The cells were then dispersed in their respective culture media. The cell suspensions were mixed with AdECM pregel solutions to achieve a final concentration of 1 × 10⁷ cells/mL. Using a fixed-volume pipette, 0.5 µL of the cell-laden droplet was added to each well of a 96-well plate at 4°C. Next, 50 µL of AdECM pregel solution without cells was added to the well using a second cartridge and incubated at 37°C for 1 h to allow gelation. After gelation, endothelial cell culture medium was added to the wells using a third cartridge to mimic the blood–brain barrier (BBB). The medium was changed every 2 or 3 days.

Anticancer drug testing

Once the patient-derived PDTS models were established, specific anticancer drugs, including osimertinib, afatinib, eribulin, docetaxel, dabrafenib + trametinib, UFT capsules, TS-1 (tegafur, gimeracil, oteracil potassium combined capsule), cyclophosphamide, vinorelbine, cisplatin, carboplatin, gemcitabine, epirubicin and regorafenib, which are listed in Table 2 below, were utilized. The dosage standards for these drugs in PDTS models have been established in previous projects and were applied in PDTS models from recruited patients in this study.

Table 2

patient list and data
S. No.	Gender	Age	Origin of the tumor	Treatment regimen	Result of the drugs test in PDTS system	Clinical outcome	Duration of follow-up (months)	Immunotherapy, angiogenesis inhibitor or cell therapy
1	Female	56	Lung CA	Osimertinib	No response	SD	15
2	Female	65	Lung CA	Afatinib	Response	SD	15
3^a	Female	56	Breast CA	First line: Eribulin	No response	PD	8
				Second line: Vinorelbine	Response	PR	6
4	Female	64	Gastric CA	UFT capsules	Response	PR	7
5	Female	48	Melanoma	Dabrafenib Mesylate + Trametinib Dimethyl Sulfoxide	No response	PR	13	Y (Cell therapy)
6^*	Female	37	Breast CA	Eribulin	Intermediate	PD	13
7	Male	69	Colon CA	TS-1	Intermediate	PD	4
8	Male	58	Esophageal scc	Methotrexate + Epirubicin	Response (Epirubicin)	PR	8
9	Male	69	Lung CA	DOCEtaxel + ramucirumab	Response (Docetaxel)	PD	7	Y (Ramucirumab)
10	Female	76	Lung CA	Osimertinib	Intermediate	PR	10
11^*	Female	39	Breast CA	Eribulin	Intermediate	PD	9
12	Male	57	NPC	Epirubicin + Methotrexate then Vincristine + Bleomycin then Cisplatin + Mitomycin C	Response (Epirubicin, Cisplatin)	PD	8
13	Female	51	Breast CA	Capecitabine + CyClophosphamide	Response (Cyclophosphamide)	PR	6.5
14	Female	63	Breast CA	Capecitabine + Vinorelbine	Response (Vinorelbine)	PD	6
15	Male	68	Lung CA	Gemcitabine + Pembrolizumab	Response (Gemcitabine)	PD	4	Y (Pembrolizumab and cell therapy)
16	Female	55	Cervical CA	Pembrolizumab + Carboplatin + Topotecan	Response (Carboplatin)	PD	3.5	Y (Pembrolizumab)
17	Male	59	Lung CA	Afatinib	Response	PR	3.5
18	Male	44	HCC	Regorafenib	No response	PD	3
Abbreviations: CA: cancer; scc: squamous cell carcinoma; HCC: hepatocellular carcinoma; PR: partial response; SD: stable disease; PD: progressive disease; PDTS: patient-derived tumor spheroid. *: No. 6 and No. 11 were the same individuals who underwent brain tumor surgery twice due to recurrent brain metastasis.

Following the establishment of the PDTS model, anticancer drugs were cocultured with the cells for an additional 2 days. The viability of the spheroids in the PDTS model was assessed using PrestoBlue HS (Invitrogen). Briefly, PrestoBlue HS was added to the medium at a ratio of 1:9, and the cells were allowed to react in the incubator for 2 hours. Subsequently, the solution was transferred to a new 96-well microplate, and fluorescence was measured using a spectrophotometer (Infinite Pro M200, Tecan, Männedorf, Switzerland) with an excitation/emission wavelength of 560/590 nm. All experiments were conducted in triplicate, and averages were recorded. The survival of spheroids encapsulated in AdECM was observed using live/dead analysis with a confocal microscope (Leica TCS SP8, Wetzlar, Germany). Live cells were stained with green fluorescent calcein acetoxymethyl (calcein AM), and dead cells were stained with red fluorescent ethidium homodimer-1 (EthD-1) to distinguish between live and dead cells. The drug test reports categorized responses as response, intermediate, or no response, based on the percentage of cell death with varying concentrations of agents. A response (cell death exceeding 30%) was considered effective. For detailed procedures, refer to the article published by Shie et al.⁷

Postsurgical management and follow-up

After surgery, participants continued their current treatment plan, which may include whole-brain radiation therapy (WBRT), targeted therapy, chemotherapy, or cell therapy in some cases, along with regular follow-up appointments to monitor their condition. The results of the anticancer drug tests were provided to physicians within 21 days for reference. Tumor status in both the brain and the original organ was assessed using computed tomography (CT) or magnetic resonance imaging (MRI) every 3 months after surgery. The endpoint of the study was patient expiration or loss to follow-up. The imaging results were evaluated by the attending physician according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1), categorizing responses as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Patients who achieved CR, PR, or SD were considered to have benefited from the drug treatment. An investigation comparing the results of the anticancer drug tests with clinical outcomes was conducted to assess the prediction accuracy of the developed PDTS model.

Author Contribution

Chun-Chung Chen and Yi-Wen Chen conceived the project, designed the study, led data interpretation and wrote the manuscript; Kai-Wen Kan and Ming-You Shie, conducted most of the experiments in culturing and characterization of the spheroids including drug response; Kai-Wen Kan contribute to tissue sections and staining; Chun-Jen Chang contributed to write the manuscript and data interpretation; Der-Yang Cho coordinated and guided the clinical study; Yu-Han Nan, Yu-Chung Juan, Chih-Hsiu Tu, Chen-Ting Yang and Wei-Lin Hsu contributed to data collection. All authors reviewed the manuscript.

Acknowledgements

There was no support to this study.

Data Availability

the datasets generated during the current study are available from the corresponding authors in resonable request.

Competing interests

The authors declare no conflicts of interest regarding this study.

Singh, K. et al. Update on the management of brain metastasis. Neurotherapeutics 19, 1772–1781 (2022).
Voest, E. E. & Bernards, R. DNA-guided precision medicine for cancer: a case of irrational exuberance? Cancer Discov. 6, 130–132 (2016).
Tentler, J. J. et al. Patient-derived tumour xenografts as models for oncology drug development. Nat. Rev. Clin. Oncol. 9, 338–350 (2012).
Tiriac, H. et al. Organoid profiling identifies common responders to chemotherapy in pancreatic cancer. Cancer Discov. 8, 1112–1129 (2018).
Tuveson, D. & Clevers, H. Cancer modeling meets human organoid technology. Science 364, 952–955 (2019).
Vlachogiannis, G. et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science 359, 920–926 (2018).
Shie, M. Y. et al. Highly mimetic ex vivo lung-cancer spheroid-based physiological model for clinical precision therapeutics. Adv. Sci. 10, e2206603 (2023).
Bray, L. J., Hutmacher, D. W. & Bock, N. Addressing patient specificity in the engineering of tumor models. Front. Bioeng. Biotechnol. 7, 217 (2019).
Azevedo, A. S., Follain, G., Patthabhiraman, S., Harlepp, S. & Goetz, J. G. Metastasis of circulating tumor cells: favorable soil or suitable biomechanics, or both? Cell Adhes. Migr. 9, 345–356 (2015).
Fidler, I. J. et al. Modulation of tumor cell response to chemotherapy by the organ environment. Cancer Metastasis Rev. 13, 209–222 (1994).
Killion, J. J., Radinsky, R. & Fidler, I. J. Orthotopic models are necessary to predict therapy of transplantable tumors in mice. Cancer Metastasis Rev. 17, 279–284 (1998).
Gould, S. E., Junttila, M. R. & De Sauvage, F. J. Translational value of mouse models in oncology drug development. Nat. Med. 21, 431–439 (2015).
Stewart, E. L. et al. Clinical utility of patient-derived xenografts to determine biomarkers of prognosis and map resistance pathways in EGFR-mutant lung adenocarcinoma. J. Clin. Oncol. 33, 2472–2480 (2015).
Gao, H. et al. High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response. Nat. Med. 21, 1318–1325 (2015).
Yuki, K., Cheng, N., Nakano, M. & Kuo, C. J. Organoid models of tumor immunology. Trends Immunol. 41, 652–664 (2020).
Ganesh, K. et al. A rectal cancer organoid platform to study individual responses to chemoradiation. Nat. Med. 25, 1607–1614 (2019).
Yao, Y. et al. Patient-derived organoids predict chemoradiation responses of locally advanced rectal cancer. Cell Stem Cell 26, 17–26.e16 (2020).
Chen, C. C. et al. Patient-derived tumor organoids as a platform of precision treatment for malignant brain tumors. Sci. Rep. 12, 16399 (2022).

No competing interests reported.

Download PDF

Editorial decision: Revision requested
20 Aug, 2024
Reviews received at journal
19 Jun, 2024
Reviewers agreed at journal
07 Jun, 2024
Reviews received at journal
28 May, 2024
Reviewers agreed at journal
15 May, 2024
Reviewers invited by journal
13 May, 2024
Editor assigned by journal
13 May, 2024
Editor invited by journal
07 May, 2024
Submission checks completed at journal
07 May, 2024
First submitted to journal
30 Apr, 2024

You are reading this latest preprint version

The preliminary study of patient-derived metastatic brain tumors in a highly mimetic ex vivo spheroid-based physiological model for clinical precision therapeutics

Status:

Version 1

Abstract

Figures

Introduction

Results

Patient no. 10

Discussion

Methods

Patients

Materials and methods in the laboratory

Decellularization of bovine adipose tissue

PDTS system

Anticancer drug testing

Postsurgical management and follow-up

Declarations

Author Contribution

Acknowledgements

Data Availability

References

Additional Declarations

Status:

Version 1