Patient-derived xenografts for individualized care in advanced sarcoma

Abstract

Background: Patients with advanced, metastatic sarcoma have a poor prognosis, and the overall benefit from the few standard-of-care therapeutics available is small. The rarity of this tumor, combined with the wide range of subtypes, leads to difficulties in conducting clinical trials. The authors previously reported the outcome of patients with a variety of common solid tumors who received treatment with drug regimens that were first tested in patient-derived xenografts using a proprietary method ("TumorGrafts").

Methods: Tumors resected from 29 patients with sarcoma were implanted into immunodeficient mice to identify drug targets and drugs for clinical use. The results of drug sensitivity testing in the TumorGrafts were used to personalize cancer treatment.

Results: Of 29 implanted tumors, 22 (76%) successfully engrafted, permitting the identification of treatment regimens for these patients. Although 6 patients died before the completion of TumorGraft testing, a correlation between TumorGraft results and clinical outcome was observed in 13 of 16 (81%) of the remaining individuals. No patients progressed during the TumorGraft-predicted therapy.

Conclusions: The current data support the use of the personalized TumorGraft model as an investigational platform for therapeutic decision-making that can guide treatment for rare tumors such as sarcomas. A randomized phase 3 trial versus physician's choice is warranted.

Keywords: TumorGraft; biomarker; chemotherapy; mice; prediction; response; sarcoma; trial.

Figure 1

This is a schematic of the TumorGraft engraftment and testing process. A piece of the patient's tumor is collected at the time of surgery and implanted into immunocompromised mice for the purpose of propagation. While the patient recovers from surgery and receives treatment with first-line therapies, the TumorGraft is expanded across more mice (generations P0-P3). These engrafted mice eventually are enrolled in a drug-screening test to determine optimal treatments (RX). Test results are presented to the patient's treating oncologist to help guide later stages of therapy.

Figure 2

Clinical and TumorGraft data are illustrated for patient POS-1119. (A) Histology of the TumorGraft reveals a dedifferentiated liposarcoma, similar to results from the patient's pathology reports. (B-D) TumorGraft sensitivity testing was performed to determine which drugs would be effective against the patient's tumor. Ruxolitinib, regorafenib, and ifosfamide significantly blocked tumor growth during TumorGraft testing. Asterisks denote significance (a single asterisk indicates P ≤ .05; double asterisks, P ≤ .01; triple asterisks, P ≤ .001). (E) Radiology reports for patient POS-1119 demonstrate a partial response after treatment with ifosfamide.

Figure 3

Clinical and TumorGraft data are illustrated for patient POS-1130. (A) Histology of the TumorGraft reveals a high-grade, pleomorphic, spindle and epithelioid sarcoma. (B,C) TumorGraft sensitivity testing was performed to determine which drugs would be effective against the patient's tumor. Everolimus, doxorubicin, eribulin, and a combination of docetaxel and gemcitabine proved effective using TumorGraft technology. Asterisks denote significance (a single asterisk indicates P ≤ .05; double asterisks, P ≤ .01; triple asterisks, P ≤ .001).

Figure 4

Clinical and TumorGraft data are illustrated for patient POS-1207. (A) Histology of the TumorGraft confirms Ewing sarcoma. (B) TumorGraft sensitivity testing was performed to determine which drugs would be effective against the patient's tumor. A combination of docetaxel, gemcitabine, and bevacizumab proved effective using TumorGraft technology. Asterisks denote significance (a single asterisk indicates P ≤ .05; double asterisks, P ≤ .01; triple asterisks, P ≤ .001). (C) Radiology reports for patient POS-1119 demonstrate a partial response after treatment with ifosfamide.

Figure 5

TumorGraft sensitivity testing is illustrated for Patient 1241 (POS-1241), who was diagnosed with metastatic myxoma. TumorGraft testing demonstrates significant tumor growth inhibition after treatment with a combination of either ifosfamide and etoposide or irinotecan and temozolomide. Asterisks denote significance (triple asterisks indicate P ≤ .001).

Figure 6

Retrospective TumorGraft testing is illustrated. (A) Retrospective TumorGraft testing for patient POS-1009 reveals significant growth reduction with a combination of gemcitabine and docetaxel. (B,C) Retrospective TumorGraft testing for patient POS-1152 indicates strong antitumor effects with either trabectidin or ifosfamide. (D) Retrospective TumorGraft testing for patient POS-1255 demonstrates that, although eribulin and sunitinib slow tumor growth relative to controls, the patient's tumor still grows, albeit more slowly. Asterisks denote significance (a single asterisk indicates P ≤ .05; double asterisks, P ≤ .01; triple asterisks, P ≤ .001).