Diagnostic assessment of osteosarcoma chemoresistance based on Virtual Clinical Trials

Abstract

Osteosarcoma is the most common primary bone tumor in pediatric and young adult patients. Successful treatment of osteosarcomas requires a combination of surgical resection and systemic chemotherapy, both neoadjuvant (prior to surgery) and adjuvant (after surgery). The degree of necrosis following neoadjuvant chemotherapy correlates with the subsequent probability of disease-free survival. Tumors with less than 10% of viable cells after treatment represent patients with a more favorable prognosis. However, being able to predict early, such as at the time of the pre-treatment tumor biopsy, how the patient will respond to the standard chemotherapy would provide an opportunity for more personalized patient care. Patients with unfavorable predictions could be studied in a protocol, rather than a standard setting, towards improving therapeutic success. The onset of necrotic cells in osteosarcomas treated with chemotherapeutic agents is a measure of tumor sensitivity to the drugs. We hypothesize that the remaining viable cells, i.e., cells that have not responded to the treatment, are chemoresistant, and that the pathological characteristics of these chemoresistant tumor cells within the osteosarcoma pre-treatment biopsy can predict tumor response to the standard-of-care chemotherapeutic treatment. This hypothesis can be tested by comparing patient histopathology samples before, as well as after treatment to identify both morphological and immunochemical cellular features that are characteristic of chemoresistant cells, i.e., cells that survived treatment. Consequently, using computational simulations of dynamic changes in tumor pathology under the simulated standard of care chemotherapeutic treatment, one can couple the pre- and post-treatment morphological and spatial patterns of chemoresistant cells, and correlate them with patient clinical diagnoses. This procedure, that we named ‘Virtual Clinical Trials’, can serve as a potential predictive biomarker providing a novel value-added decision support tool for oncologists.

Microenvironmental Niches and Sanctuaries: A Route to Acquired Resistance

“…We recently postulated a concept of Virtual Clinical Trials to assess tumor chemoresistance based on patient-specific biopsy data and computer simulations of therapeutic treatments [58]. While it is difficult and costly to perform extensive scheduling experiments in a laboratory, it is relatively easy and inexpensive to run large numbers of computational simulations to test various dosing and timing schedules of mono- and multi-drug therapies.…”

Prospective Preliminary In Vitro Investigation of a Magnetic Iron Oxide Nanoparticle Conjugated with Ligand CD80 and VEGF Antibody As a Targeted Drug Delivery System for the Induction of Cell Death in Rodent Osteosarcoma Cells

“…In both, the disease is a spontaneously occurring, primary bone tumor with often-seen complicated clinical ramifications (such as metastasis, pain, and pathological fracture) and bimodal expression. 4 …”

“…1–5 Patients with OSA have a low survival rate (15–30%) because of distant metastasis, often present at the time of diagnosis. 1,2,4,6 In addition, patients having undergone tumor excision without supplementary chemotherapy or radiation therapy have an 80% chance of developing metastatic disease. 2 Possible treatments for OSA consist of surgery, chemotherapy, and radiation therapy.…”

Assessment of patient-specific efficacy of chemo- and targeted-therapies: a micropharmacology approach

“…Virtual Clinical Trials concept The Virtual Clinical Trials concept [4] uses standard-of-care (SOC) medical histology images that are routinely collected in the clinic, advanced image analysis algorithms, and computational simulations to determine whether a patient's tumor is resistant to SOC treatments. We envision that the patient will follow the schematics presented in Figure 1.…”