Exploiting metabolic acidosis in solid cancers using a tumor-agnostic pH-activatable nanoprobe for fluorescence-guided surgery

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Abstract

Cancer cell metabolism leads to a uniquely acidic microenvironment in solid tumors, but exploiting the labile extracellular pH differences between cancer and normal tissues for clinical use has been challenging. Here we describe the clinical translation of ONM-100, a nanoparticle-based fluorescent imaging agent. This is comprised of an ultra-pH sensitive amphiphilic polymer, conjugated with indocyanine green, which rapidly and irreversibly dissociates to fluoresce in the acidic extracellular tumor microenvironment due to the mechanism of nanoscale macromolecular cooperativity. Primary outcomes were safety, pharmacokinetics and imaging feasilibity of ONM-100. Secondary outcomes were to determine a range of safe doses of ONM-100 for intra-operative imaging using commonly used fluorescence camera systems. In this study (Netherlands National Trial Register #7085), we report that ONM-100 was well tolerated, and four solid tumor types could be visualized both in- and ex vivo in thirty subjects. ONM-100 enables detection of tumor-positive resection margins in 9/9 subjects and four additional otherwise missed occult lesions. Consequently, this pH-activatable optical imaging agent may be clinically beneficial in differentiating previously unexploitable narrow physiologic differences.

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Prognostic and predictive impact of intra- and peritumoral immune infiltrates.

Wolf Fridman, Jérôme Galon, Franck Pagès … (2011)

Leukocyte infiltrates into or around tumor cell nests are found in the context of protumorigenic inflammation and anticancer immunosurveillance. Hence, the detailed composition, density, architecture, and function of leukocyte infiltrates must be analyzed to understand their prognostic impact. The ectopic presence within tumors of high endothelial venule cells, which are normally characteristic for secondary lymphoid organs, correlates with a more pronounced infiltration by T lymphocytes and has a positive predictive impact on local advanced breast cancer treated with neoadjuvant chemotherapy. Recent progress in the field indicates that immune infiltrates of the primary tumors, as well as of metastases, are not only independent prognostic biomarkers but can also constitute predictive factors, suggesting that the pretherapeutic immune response can determine the efficacy of conventional chemotherapies. Moreover, accumulating evidence indicates that chemotherapy can stimulate anticancer immune responses coupled with an increased intratumoral lymphoid infiltration, which correlates with tumor mass reduction and patient survival. Improved methods for the automation of immunohistochemistry and digitalized image analyses will pave the way to an improved understanding of the complex interplay between cancer parenchyma, stroma, and immune effectors, as well as to the routine evaluation of immune-related parameters to the clinical management of cancer patients. ©2011 AACR.

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The relevance of tumour pH to the treatment of malignant disease.

J.L. Wike-Hooley, J. Haveman, H.S. Reinhold (1984)

The wide range of tumour pH values that have been determined in human tumours is shown in Fig. 4. It can be seen that tumour pH values may be very low, or may fall in the same range as the values found in normal tissues. This means that pH-mediated modification of therapeutic effectiveness will be patient specific, rather than a general phenomenon. That the pH of the cellular environment might influence the effectiveness of various therapeutic agents is not a new idea. The data published in this field to date concerning such effects have been discussed extensively and are summarized in Table IV. Here we can see that low pH leads to decreased cell survival following treatment with hyperthermia, radiotherapy combined with hyperthermia, radiosensitizers and various chemotherapeutic agents. Conversely, low pH affords some protection against radiation and some drugs. Most of these data were, of necessity, derived from in vitro studies. In vivo studies are in most cases not feasible due to the difficulty of isolating the effect of one selected factor. Low tumour pH is, in vivo, generally assumed to be closely interlinked with tissue hypoxia and low blood-flow levels, each of which may individually influence the experimental outcome. Moreover, most of the aforementioned in vitro studies were conducted under well-oxygenated conditions. As previously mentioned, euoxic cells can, under certain conditions, maintain a pH gradient over the cell membrane. This collapses with the onset of hypoxia, leading to intracellular acidification. Low oxygen levels have been shown to be characteristic of many tumours. Within these limitations it is thus evident that tumour pH values could have far-reaching consequences for therapy. If the in vitro findings should prove to be relevant to the clinical situation various applications are possible. Pre-selection of patients less likely to respond to certain (toxic) chemotherapeutic agents, or conversely selection of agents that are more likely to be effective in the pH range of the tumour to be treated are two examples. Alternatively, the exploitation of low tumour pH values is a possibility. Agents that form or release toxic derivatives in areas of low pH, e.g., pH-sensitive liposomes, will work selectively in such areas. Tumour selective therapy may also be possible in patients with higher tumour pH values if the tumour pH can be lowered. This has been achieved experimentally by the administration of hyperthermia at temperatures above 42 degrees C, or by the administration of glucose.(ABSTRACT TRUNCATED AT 400 WORDS)

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The role of carbonic anhydrase IX in cancer development: links to hypoxia, acidosis, and beyond

Silvia Pastorekova, Robert Gillies (2019)

Cancer development is a complex process that follows an intricate scenario with a dynamic interplay of selective and adaptive steps and an extensive cast of molecules and signaling pathways. Solid tumor initially grows as an avascular bulk of cells carrying oncogenic mutations until diffusion distances from the nearest functional blood vessels limit delivery of nutrients and oxygen on the one hand and removal of metabolic waste on the other one. These restrictions result in regional hypoxia and acidosis that select for adaptable tumor cells able to promote aberrant angiogenesis, remodel metabolism, acquire invasiveness and metastatic propensity, and gain therapeutic resistance. Tumor cells are thereby endowed with capability to survive and proliferate in hostile microenvironment, communicate with stroma, enter circulation, colonize secondary sites, and generate metastases. While the role of oncogenic mutations initializing and driving these processes is well established, a key contribution of non-genomic, landscaping molecular players is still less appreciated despite they can equally serve as viable targets of anticancer therapies. Carbonic anhydrase IX (CA IX) is one of these players: it is induced by hypoxia, functionally linked to acidosis, implicated in invasiveness, and correlated with therapeutic resistance. Here, we summarize the available experimental evidence supported by accumulating preclinical and clinical data that CA IX can contribute virtually to each step of cancer progression path via its enzyme activity and/or non-catalytic mechanisms. We also propose that targeting tumor cells that express CA IX may provide therapeutic benefits in various settings and combinations with both conventional and newly developed treatments.