Adult human sarcomas. II. Medical oncology

Abstract

Human sarcoma cells can be killed by radio- and chemotherapy, but tumor cells acquiring resistance frequently kill the patient. A keen understanding of the intracellular course of oncogenic cascades leads to the discovery of small molecular inhibitors of the involved phosphorylated kinases. Targeted therapy complements chemotherapy. Oncogene silencing is feasible by small interfering RNA. The restoration of some of the mutated or deleted tumor-suppressor genes (p53, Rb, PTEN, hSNF, INK/ARF and WT) by demethylation or reacetylation of their histones has been accomplished. Genetically engineered or naturally oncolytic viruses selectively lyse tumors and leave healthy tissues intact. Adeno- or retroviral vectors deliver genes of immunological costimulators, tumor antigens, chemo- or cytokines and/or tumor-suppressor proteins into tumor (sarcoma) cells. Suicide gene delivery results in apoptosis induction. Genes of enzymes that target prodrugs as their substrates render tumor cells highly susceptible to chemotherapy, with the prodrug to be targeted intracellularly. It will be combinations of sophisticated surgical removal of the nonencapsulated and locally invasive primary sarcomas, advanced forms of radiotherapy to the involved sites and immunotherapy with sarcoma vaccines that will cure primary sarcomas. Adoptive immunotherapy with immune lymphocytes will be operational in metastatic disease only when populations of regulatory T cells are controlled. Targeted therapy with small molecular inhibitors of oncogene cascades, the driving forces of sarcoma cells, alteration of the tumor stroma from a supportive to a tumor-hostile environment, reactivation or replacement of wild-type tumor-suppressor genes, and radio–chemotherapy (with much reduced toxicity) will eventually accomplish the cure of metastatic sarcomas.

Keywords::

• chemotherapy
• gene therapy
• histone deacetylase inhibitors
• imatinib mesylate
• immunotherapy
• oncolytic viruses
• rapamycin–mTOR
• siRNA
• targeted therapy

Disclosure

The author is not paid by drug companies and has no investments in them.

Notes

*Thorax CT scans. November 1999: loculated right pleural effusion with irregular pleural thickening involving fissures; 2-cm nodule right posterior lung base abutting pleural surface; ill-defined densities right upper lung. November 2004: right pleural effusion, nodules, pulmonary densities resolved; pulmonary parenchyma clear; mediastinal lymph nodes not enlarged. February 2005: right pleural nodularity increased in size and number; no effusion; mediastinum clear. February 2005: right-sided pleural thickening and nodularity persist unchanged; no effusion; lung parenchyma clear; mediastinum clear. PET March 2005: significant hypermetabolism of multiple pleurally based masses on the right “indicative of recurrent malignancy”.

Biopsies. September 1999: anaplastic malignant tumor with spindle cell morphology in myxoid background; cytokeratins, S100, HMB-45, desmin, actin, chromogranin, α-fetoprotein, 0-13: all negative; vimentin (intermediate filament cytoskeletal protein): positive. “High-grade sarcoma”.

Consultant K Leslie, Mayo Clinics, Scottsdale, AZ USA: “desmoplastic small round cell tumor (sarcoma) highly aggressive.” March 2005: right pleural tissue with extensive giant cell reaction to refractile foreign material (talcum); no evidence of malignancy in several samples. (Marc Ladanyi’s [Memorial Sloan-Kettering, NY, USA)] description of desmoplastic small round cell tumor: “highly aggressive, poor survival.”.

Bernard Show: “Stimultate the phagocytes. Drugs are a delusion. The phagocytes are stimulated; they devour the disease; and the patient recovers.” (The Doctor's Deilemma p. 106, London, 1906).

CR: Complete remission; CT: Computed tomography; LLQ: Left lower quadrant; NED: No evidence of disease; PET: Positron emission tomography; StJH: St Joseph's Hospital.

APE: a-purinic endonuclease; CTGF: Connective tissue GF: EWS: EDwing’s sarcoma; GF: Growth factor; KS: Kaposi’s sarcoma; MMP: Metalloproteinase; OS: Osteosarcoma; PDGF: Platelet-derived growth factor; PL: antiphospholipase; RMS: Rhabdomyosarcoma; si: short interfering; SS: Synovial sarcoma; STS: Soft tissue sarcoma; VEGF: Vascular endothelial growth factor.