Drug Repurposing by Tumor Tissue Editing

Abstract

The combinatory use of drugs for systemic cancer therapy commonly aims at the direct elimination of tumor cells through induction of apoptosis. An alternative approach becomes the focus of attention if biological changes in tumor tissues following combinatory administration of regulatorily active drugs are considered as a therapeutic aim, e.g., differentiation, transdifferentiation induction, reconstitution of immunosurveillance, the use of alternative cell death mechanisms. Editing of the tumor tissue establishes new biological ‘hallmarks’ as a ‘pressure point’ to attenuate tumor growth. This may be achieved with repurposed, regulatorily active drug combinations, often simultaneously targeting different cell compartments of the tumor tissue. Moreover, tissue editing is paralleled by decisive functional changes in tumor tissues providing novel patterns of target sites for approved drugs. Thus, agents with poor activity in non-edited tissue may reveal new clinically meaningful outcomes. For tissue editing and targeting edited tissue novel requirements concerning drug selection and administration can be summarized according to available clinical and pre-clinical data. Monoactivity is no pre-requisite, but combinatory bio-regulatory activity. The regulatorily active dose may be far below the maximum tolerable dose, and besides inhibitory active drugs stimulatory drug activities may be integrated. Metronomic scheduling often seems to be of advantage. Novel preclinical approaches like functional assays testing drug combinations in tumor tissue are needed to select potential drugs for repurposing. The two-step drug repurposing procedure, namely establishing novel functional systems states in tumor tissues and consecutively providing novel target sites for approved drugs, facilitates the systematic identification of drug activities outside the scope of any original clinical drug approvals.

Peroxisome proliferator-activated receptorα/γ agonist pioglitazone for rescuing relapsed or refractory neoplasias by unlocking phenotypic plasticity

“…The novel treatment concept ‘tumor tissue editing’ adopts to the use of tissue editing techniques for correcting epigenetic or genetic aberrations in tumor tissues ( 20 ). Tumor tissue editing methods aim at therapeutically exploiting tumor phenotypes by reprogramming hallmarks of cancer ( 28 ).…”

“…As clinically shown, unlocking the tumor’s plasticity with therapy approaches editing the tumor’s growth-promoting phenotype in a therapeutically relevant way, i.e., tumor tissue editing, facilitates the successful clinical integration of combined transcriptional modulation with pioglitazone ( 20 – 24 ). Tumor tissue editing techniques concertedly reprogram hallmarks of cancer for establishing biologic hallmarks that may control tumor growth, and even induce tumor cell death ( 11 ).…”

“…Tissue editing techniques include synergistic combinations of bioactive drugs, such as metronomic low-dose chemotherapies, transcriptional modulators, i.e., pioglitazone, interferon-α, dexamethasone or all-trans retinoic acid (ATRA) and cyclooxygenase-2 (COX-2) inhibitors, and may induce long-term tumor control, objective response, even continuous complete remission (cCR) in r/r neoplasias ( 21 – 23 , 25 – 28 ). On the top, edited stress reponse pathways, referred to as non-oncogene addiction in tumor tissues, provide a novel, repurposed activity profile for approved targeted therapies ( 20 , 29 ).…”

Dormancy, stemness, and therapy resistance: interconnected players in cancer evolution

“…In particular, PPARγ agonists were shown to be effective in combination with a broad variety of systemic therapies [176]. Metabolic modulators, low-dose chemotherapy, epigenetic agents, retinoic acid derivatives, and a number of repurposed drugs have been all considered in the frame of anakoinosis, a therapeutic strategy based on tumor communicative reprogramming [177,178]. Finally, senescence modulation is attracting increasing interest in cancer treatment [179].…”

Case report: Sustained complete remission with all-oral MEPED therapy in a patient with Hodgkin’s disease developing resistance to pembrolizumab

“…Cyclooxygenase-2 (COX2) affects the accessibility of PPAR ligands. Efficacy in the use of pioglitazone in cancer can be achieved by combining it with other master modifiers - such as COX2 inhibitors ( Lüke et al, 2022 ). The use of other modulators of transcription factors such as glucocorticoids and the administration of metronome low-dose chemotherapy can produce a synergistic effect in tumor tissue ( Heudobler et al, 2018 ).…”