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High Clinical Concordance of Drug Resistance in Patient-derived Orthotopic Xenograft (PDOX) Mouse Models: First Step to Validated Precise Individualized Cancer Chemotherapy

TAKASHI HIGUCHI, NORIO YAMAMOTO, KATSUHIRO HAYASHI, SHINJI MIWA, KENTARO IGARASHI, HIROYUKI TSUCHIYA and ROBERT M. HOFFMAN
Anticancer Research October 2023, 43 (10) 4277-4284; DOI: https://doi.org/10.21873/anticanres.16622

Abstract

Finding an effective drug for individual cancer patients among the many chemotherapies available and ruling out ineffective drugs are important challenges, especially for patients with advanced cancer. To accomplish this goal, we have pioneered and developed the patient-derived orthotopic xenograft (PDOX) nude mouse model for all cancer types, enabling the discovery and evaluation of novel therapeutics, as well as individualized therapy of patients with cancer. PDOX models can more precisely reproduce the original tumor microenvironment (TME) compared to subcutaneous-implanted xenografts including patient-derived xenograft (PDX) models. The present review presents the concordance of drug resistance in individual cancer patients and their PDOX models. There are 28 PDOX publications with 12 PDOX models from patients who were treated with chemotherapy. Sixteen chemotherapeutics were administrated to these patients and all of them were clinically ineffective. In PDOX models established from these patients’ tumors, fourteen chemotherapeutics were resistant with a concordance rate of 88%. PDOX models should be established as early as possible from patients to predict and improve outcome. PDOX models mimic the clinical tumor aggressiveness, therefore enabling a high concordance with clinical outcomes. The present review shows a high concordance for drug resistance between cancer patients and their corresponding PDOX models. Future studies will include prospective clinical trials comparing both drug efficacy and resistance in patients and their PDOX models.

Key Words:

Drug resistance is a major factor preventing the cure of patients with cancer (1). The solution to drug resistance is a combination of drugs with non-overlapping mechanisms of action (1). However, it is often not possible to test every drug a patient can receive during the course of therapy, therefore individualized precision medicine using clinically-relevant mouse cancer models for drug screening is needed. Toward this goal, we have pioneered and developed the patient-derived orthotopic xenograft (PDOX) model using surgical orthotopic implantation (SOI), which mimics the clinical course of cancer. PDOX models from patients with major types of cancers, including breast (2, 3), colon (4, 5), ovarian (6), cervical (7, 8), pancreatic (9, 10), melanoma (11, 12), gastrointestinal stromal tumor (GIST) (13), stomach (14), osteosarcoma (15, 16), and soft-tissue sarcomas (17-19), have been established by us and used to discover many effective chemotherapies.

In addition, we have developed a co-transplantation technique of surrounding normal and tumor tissues, the Hozumi method, to increase the uptake rates of patient tumors in nude mice, which is a limitation of patient-derived xenografts (20). The Hozumi method comprises co-implanting the surgical tumor along with large amounts of surrounding normal tissue into a pocket made in the subcutaneous space of nude mice (20). The uptake rates were up to 66% using the Hozumi method compared to only 14% using the conventional method of implanting the tumor specimen without the surrounding normal tissue (20). The Hozumi method allows for the widespread dissemination of individualized mouse tumor models for patients and has the potential to screen not only effective drugs for each patient, but also ineffective drugs. The potential drug toxicity and morbidity of ineffective chemotherapies in patients can be avoided using PDOX models.

In the present review, we demonstrate clinical concordance of drug resistance in individual patients and their PDOX models.

Ewing Sarcoma (ES)

Ewing sarcoma (ES) is the second-most common malignant primary bone tumor occurring in adolescents and young adults (21). Standard treatment for metastatic and non-metastatic disease consists of chemotherapy and local therapy, including surgery and radiotherapy (21). Recurrent ES is associated with poor prognosis, and treatment options are limited (21).

An ES tumor from the right chest wall of a 46-year-old female patient was resected in the Department of Surgery, University of California, Los Angeles (UCLA) (22-28). Neoadjuvant chemotherapy with doxorubicin (DOX), vincristine (VCR), and cyclophosphamide (CPA), had been previously administered to the patient. A fresh tumor tissue specimen from the ES of the right chest wall was implanted subcutaneously in nude mice (22-28). The established tumors were harvested and minced into small fragments. A single tumor fragment was orthotopically implanted into the layer between the pectoral muscle and intercostal muscle in the right chest wall of the nude mouse to establish an ES PDOX model (22-28).

In this ES PDOX model, DOX, which was not effective in the patient, was not able to inhibit the PDOX tumor growth, showing concordance with patient results (22, 24, 26, 28). In contrast, we demonstrated many promising drugs using the ES PDOX model such as palbociclib (PAL) (28), linstinib (OSI-906) (28), pazopanib (PAZ) (25), regorafenib (RGF) (22), eribulin (ERI) (24), combinations of temozolomide (TMZ)-irinotecan (CPT-11) (25), gemcitabine (GEM)-docetaxel (DOC) (25), and experimental agents such as recombinant methioninase (rMETase) (23), Salmonella typhimurium A1-R (S. typhimurium A1-R) (23, 26), rMETase-S. typhimurium A1-R (23), and DOX-S. typhimurium A1-R (26) (Table I).

View this table:
Table I.

Clinical concordance of drug resistance in patients and PDOX models established from the patients.

Follicular Dendritic-cell Sarcoma (FDCS)

Follicular dendritic-cell sarcoma (FDCS) is a rare tumor that arises from follicular dendritic cells (29, 30). Responses to combination chemotherapy with CPA, DOX, VCR, and prednisone (PSL) are often insufficient (29, 30). A female patient had previously received postoperative adjuvant radiotherapy to the left lower extremity after resection of the primary lesion and 4 cycles of chemotherapy with DOX and CPA for the recurrent lesion (29, 30). Chemotherapy was discontinued due to medical comorbidity and intolerance to treatment (29, 30). Surgical resection of the recurrent FDCS was performed in UCLA (29, 30). An FDCS PDOX was established on the right thigh where a single tumor fragment was implanted orthotopically into the biceps femoris of nude mice (29, 30). DOX did not inhibit the PDOX growth, which is concordant with the clinical results (29, 30). However, we found that TMZ (30) and S. typhimurium A1-R with/without DOX or dactolisib (BEZ235) (29) were effective on the FDCS PDOX tumor (Table I).

Osteosarcoma

Osteosarcoma is the most-common primary bone tumor (15). DOX, cisplatinum (CDDP), ifosfamide (IFO), and methotrexate (MTX) are first-line therapies for osteosarcoma (15). However, osteosarcoma frequently develops resistance to these chemotherapies resulting in tumor recurrence, often fatal to the patients (31).

We have previously obtained recurrent tumors from patients who failed to respond to initial chemotherapy and established two osteosarcoma PDOX models. The first osteosarcoma PDOX was established from a chondroblastic osteosarcoma that originated in the distal femur of a 16-year-old patient who received neoadjuvant chemotherapy containing CDDP, DOX, MTX, IFO, and etoposide (VP-16), and surgery at UCLA (32). After one year, lung metastases were found and metastasectomy was performed. A tumor specimen from the metastasectomy was obtained to establish an osteosarcoma PDOX model (32). The osteosarcoma PDOX model was established by implanting the tumor fragment orthotopically into a space in the distal femur generated by an osteotomy of the lateral femoral condyle (32). CDDP and DOX were administrated to the osteosarcoma PDOX models in several study series, but they did not inhibit the tumor growth, which is concordant with the clinical results (32-39). However, we found that trabectedin (TRAB) (36), TMZ (36), GEM-DOC (34), ERI (37), everolimus (EVL)-PAZ (38), TMZ-CPT-11 (34), PAL-EVL (39), S. typhimurium A1-R (32), an rMETase-S. typhimurium A1-R combination (33), and an anionic platinum complex (Pt3) (35), an experimental drug, were effective in this osteosarcoma PDOX model (Table I).

A second osteosarcoma PDOX model was established from a 23-year-old patient with femoral osteosarcoma who underwent surgery for tibia-bone metastasis after CDDP, MTX, DOX combination chemotherapy (15, 16). The surgical specimen was used for establishing an osteosarcoma PDOX by orthotopic implantation as mentioned above. CDDP was ineffective in this osteosarcoma PDOX model, which is concordant with the clinical results (Figure 1) (16). RGF, in contrast, was highly effective and can be used in clinical practice (16) (Table I).

Figure 1.
Figure 1.

A representative PDOX study. An osteosarcoma PDOX model was established from a 23-year-old patient with femoral osteosarcoma who underwent surgery for tibia-bone metastasis after cisplatinum (CDDP)-containing chemotherapy (16). (A) The line graphs show the tumor volume at each time point after treatment initiation relative to the initial tumor volume for each group. There was no significant difference between the control group and CDDP-treated group (p=0.34), showing CDDP resistance in the osteosarcoma PDOX model, which was concordant to the clinical result. (B, C) Representative photographs of the control or CDDP-treated osteosarcoma PDOX mouse models (16). Arrows show the margin of the tumors. (D, E) Hematoxylin- and eosin-stained sections of control and CDDP-treated tumors (16). Both sections consist of high-density viable malignant cells. Scale bars: 100 μm.

Undifferentiated Soft-tissue Sarcoma (USTS)

Undifferentiated soft-tissue sarcoma (USTS) is the most-common type of soft-tissue sarcoma observed in adults (40). DOX is a first-line chemotherapy for USTS. However, the percentage of USTS patients who have a complete response is very small (40). A 59-year-old patient with USTS of the thigh received DOX, and IFO, followed by radiation (19, 41). However, the tumor continued to grow, and the patient underwent tumor resection from which a PDOX was established (19, 41). The patient subsequently succumbed to the disease (19, 41). The USTS PDOX model was established by surgical orthotopic implantation as mentioned for the FDCS PDOX above (19, 41). DOX was ineffective on this PDOX model, which is concordant with the clinical results (19, 41). In contrast, we found that both TEM and GEM-DOC were effective in the USTS PDOX model (19, 41). In addition, a 62-year-old female patient, with USTS of the upper extremity, previously failed PAZ and GEM-DOC, then underwent tumor resection from which a PDOX was established (19, 41). PAZ and GEM-DOC were ineffective in the USTS PDOX model, which is concordant with the clinical results (19, 41). In contrast, TEM arrested the growth of the USTS PDOX model (19, 41) (Table I).

Synovial Sarcoma (SS)

Synovial sarcoma (SS) is an aggressive sarcoma subtype that accounts for 10% of all soft-tissue sarcomas, predominantly occurring in younger adults compared to other sarcomas (42). SS arises almost anywhere in the body and has high tendency to metastasize, and is recalcitrant to chemotherapy, including first-line DOX (42). A 45-year-old male with primary SS on the lower leg underwent surgical resection at UCLA (43-45). The patient received neo-adjuvant DOX-based chemotherapy prior to surgery (43-45). An SS PDOX model was established by orthotopic implantation as with the FDCS and the USTS PDOX models (43-45). DOX was ineffective in three studies, which is concordant with the clinical results (43-45). In contrast, PAZ and an rMETase-DOX combination with/without caffeine were highly effective on this PDOX model (43-45) (Table I).

Pleomorphic Liposarcoma

Pleomorphic liposarcoma (PLPS) accounts for only 5%–15% of all liposarcomas and has high metastatic potential (46). Both radiation and chemotherapy are not effective for advanced PLPS, which requires precision medicine (46). A 68-year-old patient diagnosed with a recurrent PLPS of the upper arm, previously underwent surgical resection at the UCLA medical center (47-49). The patient received multiple resections, chemotherapies including DOX, DOC, and IFO, and radiotherapy after the recurrence. Surgical resection of the recurrent right-arm PLPS was performed, and the surgical specimen was used for establishing a PLPS PDOX model, using the same technique as for the other soft-tissue sarcomas (STS) (47-49). In this PLPS PDOX model, DOX was found ineffective in several studies, which is concordant with the patient response, while TRAB, PAZ and S. typhimurium A1-R were effective (47-49) (Table I).

Leiomyosarcoma

Leiomyosarcoma accounts for 10% of all STS occurring often in a lower extremity and other places in the body such as the retroperitoneum, uterus, breast, and intracranially (50). Leiomyosarcoma has a poor prognosis, frequent recurrence, and low response to currently-available chemotherapies (50). A patient had a high-grade leiomyosarcoma in the thigh. After chemotherapy (2 cycles of GEM-DOC) and radiotherapy, surgical resection was performed at UCLA (50). A surgical specimen was used for the establishment of a leiomyosarcoma PDOX model. One year postoperatively, the patient developed a local recurrence (50). In this leiomyosarcoma PDOX model, DOX, PAZ, OLA, and an OLA-DOX combination, which are standard chemotherapies against STS, were ineffective (50) (Table I). However, a GEM-DOC combination, which failed in the patient, arrested the PDOX growth (50). However, only two cycles of GEM-DOC were used on the patient, a lower number of cycles than standard chemotherapy, and more cycles of GEM-DOC might have been effective in the patient.

Gastrointestinal Stromal Tumor (GIST)

Gastrointestinal stromal tumor (GIST) is a rare type of sarcoma derived from the muscle layer of the gastrointestinal tract (13, 14). Most GIST tumors have a mutation in the receptor tyrosine kinase c-kit in exons 11 and 9. A tyrosine-kinase inhibitor, imatinib (IMT), is first-line therapy for inoperable cases (51).

A patient with abdominal GIST received curative-intent surgery in UCLA (13, 14). The GIST recurred regionally, and the recurrent site was resected after neoadjuvant chemotherapy with IMT (13, 14). The GIST PDOX was established by orthotopic implantation in the anterior gastric wall (13, 14).

IMT was ineffective on this PDOX model, which is concordant with the clinical results (13, 14). Other tyrosine-kinase inhibitors were tested in this IMT-resistant PDOX model. The results showed that sunitinib (SUN) and RGF were effective, but PAZ was not effective (13, 14).

Colorectal Carcinoma

The liver is the most common site of metastases for colorectal cancer (52). The patients who have unresectable liver metastases are treated with chemotherapy and have a poor outcome (52). Oxaliplatinum (OXP)-based chemotherapy is one of the most frequently-used therapeutic strategies (52). OXP combined with 5-fluorouracil (5-FU) has increased the survival rate in patients with colorectal carcinoma (53).

A patient diagnosed with colorectal-cancer liver metastasis, who had received neoadjuvant chemotherapy, underwent surgery at the University of California, San Diego (UCSD) (54). A colorectal-cancer liver-metastasis PDOX model, using the surgical specimen, was established with the following procedure: A 2-cm incision was performed on the upper abdomen through the skin, fascia, and peritoneum to expose the liver, a 5-mm incision was made in the left lobe of the liver, and a small tumor fragment was inserted (54). The combination of 5-FU and OXP was found to be ineffective in the PDOX model, which is concordant with the clinical results (54). However, adding oral-rMETase to 5-FU+OXP overcame the drug-resistance in the colorectal-cancer PDOX model (54) (Table I).

Matrix-producing Tripe-negative Breast Carcinoma (MPBC)

Matrix-producing breast cancer (MPBC) is a rare histologic type of breast cancer, occurring in 0.03-0.2% of breast cancer cases worldwide (3). MPBC is characterized by direct invasion to muscle cartilage or bone matrix without involvement of spindle-cell components (3). The 5-year survival rate for MPBC patients is reported to be 68%, which is worse than that of common invasive ductal breast cancer (3).

A 40-year-old woman, who presented with a left-breast mass was diagnosed with breast cancer and underwent surgical resection at Kawasaki Medical School (2). The surgical specimen was pathologically diagnosed as MPBC and used for MPBC PDOX establishment by orthotopic implantation to a mammary gland of the mouse (2). The patient received four courses of epirubicin (EPR) and CPA, followed by weekly paclitaxel (PTX) postoperatively (2). Metastases to the ovary, which was resected surgically, and to a mediastinal lymph-node, occurred (2). The patient then received a PTX-bevacizumab (BEV) combination, but brain metastases were found, which were treated with radiotherapy (2). At this time, the results from the MPBC PDOX model became available and showed that neither PTX nor BEV inhibited the PDOX growth, which is concordant with the patient’s treatment results (2). ERI regressed the PDOX tumors, but vinorelbine (VRL) and olaparib (OLA) did not (2). The patient received one course of ERI. However, rapid enlargement of the thyroid and cervical and mediastinal lymph nodes was noted, causing tracheal stenosis (2). It was thought that the ERI was administered too late to be effective (2). Subsequently, the patient was treated with atezolizumab (Atezo) and nab-paclitaxel (nab-PTX), based on PD-L1 positivity of the metastases, which were also ineffective (2) (Table I). The patient died of disease eight months after recurrence (2).

Conclusion

There are 28 PDOX publications with 12 PDOX models established from patients who were treated with chemotherapy. Fourteen chemotherapies or combinations of drugs were tested on the PDOX models. Twelve of them were resistant both in the patients and the PDOX models. Two of them were sensitive in PDOX models but not in the patients. However, it is unlikely that the duration and timing of administration of these chemotherapies, effective in the PDOX models, were appropriate to become effective in the patients. The concordance rate was 88% (14/16).

The PDOX model accurately represents the tumor microenvironment, therefore correlates well with patient drug responsiveness. With the recent development of the Hozumi method, which has greatly increased the frequency of PDOX establishment by our laboratory, it is expected that more PDOX models will be established in the future to identify both effective and ineffective agents for each patient. To improve the prognosis of cancer patients who have failed standard treatment, there is a need to use the highly-precise drug sensitivity results of the PDOX model, as presented in this review, as early as possible in the course of a patient’s disease.

Despite $160 billion dollars allocated to the US National Cancer Intitute (NCI) since 1971, the 5-year survival rate for pancreatic cancer is 12%; 14% for metastatic colon cancer. The two-year survival rate for small-cell lung cancer is less than 20% (55). The survival rate for glioblastoma is 4.6% (56). Use of the PDOX model for patients for drug screening should increase the survival rate.

Acknowledgements

The present paper is dedicated to the memory of A.R. Moossa, MD, Sun Lee, MD, Gordon H. Sato, Ph.D, Professor Li Jiaxi, Masaki Kitajima, MD, Joseph R. Bertino, MD, Shigeo Yagi, PhD, and J.A.R Mead, Ph.D.

Footnotes

  • Authors’ Contributions

    Conception and design: TH and RMH. Acquisition, analysis, and interpretation of data: TH, NY, KH, SM, and KI. Writing, review, and revision of the article: TH and RMH.

  • Conflicts of Interest

    AntiCancer Inc. uses PDOX models for contract research. TH, NY, KH, SM, KI, and RMH are or were unsalaried associates of AntiCancer Inc. There are no other competing financial interests.

  • Received August 2, 2023.
  • Revision received August 28, 2023.
  • Accepted August 29, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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High Clinical Concordance of Drug Resistance in Patient-derived Orthotopic Xenograft (PDOX) Mouse Models: First Step to Validated Precise Individualized Cancer Chemotherapy
TAKASHI HIGUCHI, NORIO YAMAMOTO, KATSUHIRO HAYASHI, SHINJI MIWA, KENTARO IGARASHI, HIROYUKI TSUCHIYA, ROBERT M. HOFFMAN
Anticancer Research Oct 2023, 43 (10) 4277-4284; DOI: 10.21873/anticanres.16622
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