Limiting tumor seeding as a therapeut... - Advanced Prostate...

Advanced Prostate Cancer

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Limiting tumor seeding as a therapeutic approach for metastatic disease

5 years ago•7 Replies

New study below [1].

Here is another new paper that I find encouraging. As with insulin resistance, which has been a major target for me for many years, preventing metastasis after metastasis has already occurred has also been an important concern.

"The long reigning concept that the horse is out of the barn is fading and there is confidence that counteracting tumor seeding as a way of decelerating disease progression will finally loose its aura of a mostly futile endeavor."

"From a clinical standpoint, the detection of metastatic lesions has been historically interpreted as a critical turning point. At this stage a patient was considered lost to the grip of the disease and only provided palliative treatments; the intent to cure had been abandoned. Even today, with the expanded arsenal of newly developed therapeutics at our disposition, in most instances the goal is an extension of life expectancy on the order of months. There is neither anticipation for a definitive and lasting clinical resolution, nor true commitment to tailored drug development (Steeg, 2016). Understandably, this scenario is an enormous source of frustration for both clinicians and patients. Clinical scenarios involving prostate or breast adenocarcinomas are especially subject to this impasse. In the vast majority of these cases, radical ablation of the neoplastic mass is achieved by local modalities such as surgery and/or radiation therapy, but approximately 30% of cases will eventually develop metastases to which they will inevitably succumb (Brook, Brook, Dharmarajan, Dass, & Chan, 2018; Crawford, Petrylak, & Sartor, 2017).

"The pursuit of therapies intended to avert tumor seeding has been traditionally thwarted by the long-held view that, upon diagnosis of metastasis, cancer spreading had already occurred over the course of many years while the primary tumor was clinically undetected. In line with this notion, secondary lesions which have emerged after the eradication of the primary neoplasia are widely perceived as the result of DTCs resuming growth after months or years of proliferative quiescence (Morrissey, Vessella, Lange, & Lam, 2016). The triggers for the transition from dormancy to active proliferation are mostly still undefined; how-ever, experimental and clinical evidence indeed supports tumor dormancy as a cause for delayed appearance of metastases (Sosa, Bragado, & Aguirre-Ghiso, 2014). Currently, the primary aim of drug development and clinical efforts is to reduce volume and decelerate growth of detectable tumors, and by the same token also prevent the expansion of smaller and still undetectable malignant foci into larger tumors. However, recent studies have provided convincing genomic evidence that tumor cells may also depart from established metastatic tumors, entering the blood and spreading throughout the body as secondary CTCs (Micalizzi, Maheswaran, & Haber, 2017) to seed either new lesions (reseeding) or pre-existing metastatic lesions (cross-seeding). Though we are currently working to improve our understanding of the mechanisms regulating these events, it is easy to envision how reseeding could be responsible for the numerical expansion of the few lesions commonly detected in early metastatic patients, thereby hastening clinical progression towards an unfavorable ending."

-Patrick

[1] Full text: ncbi.nlm.nih.gov/pmc/articl...

ncbi.nlm.nih.gov/pubmed/308...

Pharmacol Ther. 2019 Jul;199:117-128. doi: 10.1016/j.pharmthera.2019.03.007. Epub 2019 Mar 12.

Limiting tumor seeding as a therapeutic approach for metastatic disease.

Worrede A1, Meucci O1, Fatatis A2.

Author information

Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N. 15(th) Street, Philadelphia, PA, USA.

Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N. 15(th) Street, Philadelphia, PA, USA; Program in Prostate Cancer, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. Electronic address: af39@drexel.edu.

Abstract

Here we propose that therapeutic targeting of circulating tumor cells (CTCs), which are widely understood to be the seeds of metastasis, would represent an effective strategy towards limiting numerical expansion of secondary lesions and containing overall tumor burden in cancer patients. However, the molecular mediators of tumor seeding have not been well characterized. This is in part due to the limited number of pre-clinical in vivo approaches that appropriately interrogate the mechanisms by which cancer cells home to arresting organs. It is critical that we continue to investigate the mediators of tumor seeding as it is evident that the ability of CTCs to colonize in distant sites is what drives disease progression even after the primary tumor has been ablated by local modalities. In addition to slowing disease progression, containing metastatic spread by impeding tumor cell seeding may also provide a clinical benefit by increasing the duration of the residence of CTCs in systemic circulation thereby increasing their exposure to pharmacological agents commonly used in the treatment of patients such as chemotherapy and immunotherapies. In this review we will examine the current state of knowledge about the mechanisms of tumor cells seeding as well as explore how targeting this stage of metastatic spreading may provide therapeutic benefit to patients with advanced disease.

KEYWORDS:

CX3CR1; Chemokines; Integrins; Metastasis; Seeding; Selectins

PMID: 30877019 PMCID: PMC6571062 DOI: 10.1016/j.pharmthera.2019.03.007

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pjoshea13

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