Not only tumor but also therapy heterogeneity

Garattini, Silvio; Nerini, Ilaria Fuso; D’Incalci, Maurizio

doi:10.1093/annonc/mdx646

Cited by 20 publications

(21 citation statements)

References 59 publications

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“…In most papers, when it is reported about ITH, it is mostly dealt with clonal genetic evolution only, but ITH itself is a very complex matter because it is related to different sources and shows different patterns. Recently, also heterogeneity of drug distribution has been shown to be relevant in cancer treatment ( 9 ). There are several types of ITHs that can be observed on the morphological–histological and molecular level (Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Overview on Clinical Relevance of Intra-Tumor Heterogeneity

2018

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Today, clinical evaluation of tumor heterogeneity is an emergent issue to improve clinical oncology. In particular, intra-tumor heterogeneity (ITH) is closely related to cancer progression, resistance to therapy, and recurrences. It is interconnected with complex molecular mechanisms including spatial and temporal phenomena, which are often peculiar for every single patient. This review tries to describe all the types of ITH including morphohistological ITH, and at the molecular level clonal ITH derived from genomic instability and nonclonal ITH derived from microenvironment interaction. It is important to consider the different types of ITH as a whole for any patient to investigate on cancer progression, prognosis, and treatment opportunities. From a practical point of view, analytical methods that are widely accessible today, or will be in the near future, are evaluated to investigate the complex pattern of ITH in a reproducible way for a clinical application.

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Section: Introductionmentioning

confidence: 99%

Overview on Clinical Relevance of Intra-Tumor Heterogeneity

2018

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“…The later the tumor has been diagnosed the higher degree of intra-tumoral diversity is expected [13]. Heterogeneity happens latitudinally between tumors from different patients (inter-patient heterogeneity) and longitudinally in the tumor (and metastases) of the same patient (intra-patient heterogeneity) [20]. A well-described example for heterogeneity is the hepato-cellular carcinoma (HCC) with a high degree of longitudinal heterogeneity between patients as well as latitudinal heterogeneity within the same tumor of an individual patient [21].…”

Section: Intra-tumor Heterogeneity-the Challenge Of Treating "Many Cancers In One"mentioning

confidence: 99%

Precision Oncology Beyond Genomics: The Future Is Here—It Is Just Not Evenly Distributed

Pfohl

Pflaume²,

Regenbrecht

et al. 2021

Cells

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Cancer is a multifactorial disease with increasing incidence. There are more than 100 different cancer types, defined by location, cell of origin, and genomic alterations that influence oncogenesis and therapeutic response. This heterogeneity between tumors of different patients and also the heterogeneity within the same patient’s tumor pose an enormous challenge to cancer treatment. In this review, we explore tumor heterogeneity on the longitudinal and the latitudinal axis, reviewing current and future approaches to study this heterogeneity and their potential to support oncologists in tailoring a patient’s treatment regimen. We highlight how the ideal of precision oncology is reaching far beyond the knowledge of genetic variants to inform clinical practice and discuss the technologies and strategies already available to improve our understanding and management of heterogeneity in cancer treatment. We will focus on integrating multi-omics technologies with suitable in vitro models and their proficiency in mimicking endogenous tumor heterogeneity.

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“…Tumor heterogeneity, including that of drug distribution, is an inevitable obstacle limiting treatment efficacy (39,40). In TRT, the heterogeneous ITD of radiocompounds, due at least in part to the intrinsically heterogeneous ITD of targets (e.g., different antigen expression levels among cancer cells) as well as the influence of the tumor microenvironment, can cause non-uniform delivery of cytocidal radiation throughout the tumor mass, resulting in a non-uniform therapeutic response.…”

Section: B)mentioning

confidence: 99%

Radiotheranostic Agent 64Cu-cyclam-RAFT-c(-RGDfK-)4 for Management of Peritoneal Metastasis in Ovarian Cancer

Jin

Tsuji

Degardin

et al. 2020

Clinical Cancer Research

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Ovarian cancer peritoneal metastases (OCPMs) are a pathophysiologically heterogeneous group of tumors that are rarely curable. V3 Integrin (V3) is overexpressed on tumoral neovessels and frequently on ovarian cancer cells.Here, using two clinically relevant V3-positive OCPM mouse models, we studied the theranostic potential of an V3-specific radiopeptide, 64 Cu-cyclam-RAFT-c(-RGDfK-)4 ( 64 Cu-RaftRGD), and its intra-and intertumoral distribution in relation to the tumor microenvironment.Experimental Design: V3-Expressing peritoneal and subcutaneous models of ovarian carcinoma (IGR-OV1 and NIH:OVCAR-3) were established in nude mice. 64 Cu-RaftRGD was administered either intravenously or intraperitoneally. We performed intratumoral distribution (ITD) studies, PET/CT imaging and quantification, biodistribution assay and radiation dosimetry, and therapeutic efficacy and toxicity studies.Results: Intraperitoneal administration was an efficient route for targeting 64 Cu-RaftRGD to OCPMs with excellent tumor penetration. Using the fluorescent surrogate Cy5.5-RaftRGD in our unique high-resolution multifluorescence analysis, we found that the ITD of 64 Cu-RaftRGD was spatially distinct from but complementary to that of 6 hypoxia. 64 Cu-RaftRGD-based PET enabled clear visualization of multiple OCPM deposits and ascites; biodistribution analysis demonstrated an inverse correlation between tumor uptake and tumor size (1.2-17.2 mm). 64 Cu-RaftRGD at a radiotherapeutic dose (148 MBq/0.357 nmol) showed antitumor activities by inhibiting tumor cell proliferation and inducing apoptosis, and negligible toxicity. Conclusions:Collectively, these results demonstrate the all-in-one potential of 64 Cu-RaftRGD for imaging-guided radiotherapy of OCPM by targeting both tumoral neovessels and cancerous cells. Based on the ITD finding, we propose that pairing V3and hypoxia-targeted radiotherapies could improve therapeutic efficacy by overcoming the heterogeneity of ITD encountered with single-agent treatments.

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Not only tumor but also therapy heterogeneity

Cited by 20 publications

References 59 publications

Overview on Clinical Relevance of Intra-Tumor Heterogeneity

Overview on Clinical Relevance of Intra-Tumor Heterogeneity

Precision Oncology Beyond Genomics: The Future Is Here—It Is Just Not Evenly Distributed

Radiotheranostic Agent 64Cu-cyclam-RAFT-c(-RGDfK-)4 for Management of Peritoneal Metastasis in Ovarian Cancer

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