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.

The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond

“…I trust that this Special Issue has provided sufficient insight for the reader to elaborate or debate on the main conclusion that my colleague and I have reached [ 12 ]. Namely, that “there is urgent need for designing preclinical anticancer assays (both cell-based and animal models) and treatment strategies that recapitulate the degree of complexity that exists within an individual solid tumor.…”

“…In our most recent review [ 12 ], published in part 2 of this Special Issue [ 13 ], we discussed the reasons for continuing failures in cancer therapy, whether misleading/inappropriate preclinical assays are to be blamed for this “failed medicine,” and whether some modern therapies (with or without surgery) cause more harm than benefit in the treatment of patients with solid tumors. We provided a summary of editorials/presentations by accomplished oncologists on a number of important issues that have hampered progress in cancer therapy.…”

Computational Biology Helps Understand How Polyploid Giant Cancer Cells Drive Tumor Success

“…Computational tools provide ideal support for understanding self-organization in face of cellular chaos, linked to the complex genomic functioning of the polyploid cells [ 172 , 173 ]. Single-cell RNA sequencing approaches will increasingly add new light to polyploidy, as shown in studies on hypertranscription [ 164 , 172 , 174 ].…”

“…In the long term, an increasingly prominent role for bioinformatics in elucidating polyploidy in tumors is expected. To achieve this goal, scientists from different fields are expected to come together to understand, tame, and fight cancer [ 172 , 173 ].…”

Therapeutic cancer vaccines: advancements, challenges, and prospects

“…1 Conventional cancer therapies, including surgical interventions, radiotherapy, and chemotherapy, are substantially toxic and exhibit restricted applicability, thereby underscoring the urgency for developing more efficacious cancer treatment modalities. 2 Current relevant studies suggest that cancer progressing is highly associated with "cancer immunoediting". This dynamic interplay indicates that the immune system is able to eradicate nascent cancer cells by recognizing mutated oncogenic genes or foster an immunosuppressive microenvironment conducive to tumor proliferation.…”