What Are the Reasons for Continuing Failures in Cancer Therapy? Are Misleading/Inappropriate Preclinical Assays to Be Blamed? Might Some Modern Therapies Cause More Harm than Benefit?

Abstract

Over 50 years of cancer research has resulted in the generation of massive amounts of information, but relatively little progress has been made in the treatment of patients with solid tumors, except for extending their survival for a few months at best. Here, we will briefly discuss some of the reasons for this failure, focusing on the limitations and sometimes misunderstanding of the clinical relevance of preclinical assays that are widely used to identify novel anticancer drugs and treatment strategies (e.g., "synthetic lethality"). These include colony formation, apoptosis (e.g., caspase-3 activation), immunoblotting, and high-content multiwell plate cell-based assays, as well as tumor growth studies in animal models. A major limitation is that such assays are rarely designed to recapitulate the tumor repopulating properties associated with therapy-induced cancer cell dormancy (durable proliferation arrest) reflecting, for example, premature senescence, polyploidy and/or multinucleation. Furthermore, pro-survival properties of apoptotic cancer cells through phoenix rising, failed apoptosis, and/or anastasis (return from the brink of death), as well as cancer immunoediting and the impact of therapeutic agents on interactions between cancer and immune cells are often overlooked in preclinical studies. A brief review of the history of cancer research makes one wonder if modern strategies for treating patients with solid tumors may sometimes cause more harm than benefit.

Keywords: anastasis; apoptosis; cancer therapy; immune system; intratumor heterogeneity; multiwell plate viability assays; polyploid giant cancer cells; preclinical assays; senescence.

Figure 1

Cartoon illustrating the role of polyploid/multinucleated giant cancer cells (PGCCs) in tumor response to anticancer agents. Although anticancer treatment results in initial tumor shrinkage and a dormant state several weeks post-treatment (e.g., ~35 days in a rat colon carcinoma model [67]), it also triggers the creation of PGCCs that give rise to therapy resistant and tumor repopulating progeny through neosis (nuclear budding and bursting), depolyploidization involving meiosis and self-renewal genes, and sub-genome transmission (transfer of nuclear material into surrounding cells via cytoplasmic tunnels). For further details, please consult [50].

Figure 2

(A) Oversimplified (old) strategy for eradicating solid tumors through repeated doses of radiotherapy, chemotherapy, and other means (e.g., targeted therapies) when used singly or in various combinations; (B) Complex heterogeneity within an individual solid tumor (adapted from [91]).