Projects

Clinical trials:

Project | 01
Project | 01
 
Recent clinical trials:
Perioperative blockade of adrenergic and COX2 signalling in cancer patients

Based on our transnational studies and the work of other groups, indicating the metastasis-promoting effects of catecholamines (CAs) and prostaglandins (PGs) during the perioperative period (see below), we have conducted two biomarker clinical trials in breast cancer and in colorectal cancer (CRC) patients, testing the efficacy of attenuating adrenergic and COX2 signalling during the short perioperative period. We have now completed two clinical trials, including 3-year follow-up in CRC patients, and have obtained promising short-term outcomes of the drug treatment (propranolol and etodolac), including: (i) a high safety profile and minimal adverse effects on patients’ well-being, (ii) a reversal of epithelial-to-mesenchymal transition (EMT) and favourable changes in pro-metastatic and pro-inflammatory transcription factors in the excised breast/colon cancer tissue, and (iii) a trend towards improves 3-year DFS in CRC patients (p=.054) (large but statistically-insignificant improvement). Our studies are the first to test such a perioperative approach in cancer patients. Our findings have now been published in three peer-reviewed papers in prestigious journals and laid the foundation for conducting large clinical trials aiming to reduce recurrence rates and improve long-term cancer survival in several types of metastasizing cancers.

Project | 02
Project | 02
Three ongoing clinical trials

Based on our above promising findings, we are now running two similar, but larger, clinical trials in several medical centers in Israel. The first is in CRC patients, and the second is in operated pancreatic cancer patients (see website** - add link). In addition, we are conducting a clinical trial in breast cancer patients, treating women with a psychological-behavioral intervention to reduce perioperative stress responses. These studies are conducted in collaborations with surgeons, oncologists, medical staff, psychologist and other scientists, prominent among them are Dr. Zmora and Dr. Cole.

Project | 03
Project | 03
 
Planned clinical trials

We are in the process of devising and initiating clinical trials to treat cancer patients with inoperable cancer or with inoperable metastatic disease with a similar combination of propranolol and etodolac, aiming to slow-down or halt the progression of cancer.

Ongoing studies employing animal models:

Project | 01
Project | 01
 
The use of immune stimulatory approaches during the perioperative period: Medical feasibility, deleterious effects of psychological stress, and synergism with blockade of surgery-induced stress-inflammatory responses

To promote the ability of patients to eliminate or control residual disease following primary tumor excision, we sought to potentiate anti-metastatic immune mechanisms during the critical perioperative period. This approach is rarely used perioperatively given contraindications to surgery. Thus, we adopted novel immune-stimulating that are known to have minimal adverse effects agents (e.g., activating TLR9 using CpG-C), and studied them during the critical perioperative period. Outcomes indicate marked improvements in long-term cancer outcomes in several models of cancer metastasis, specifically using CpG-C to prevent liver metastasis of colorectal cancer, and lung metastasis of various malignancies.

We also found that psychological stress jeopardizes the efficacy of immune stimulation and we are currently testing prophylactic pharmacological approaches to overcome such effects that are expected in the stressful clinical setting in cancer patients. Last, in order to protect activated immunocytes from the immune suppressive effects of surgery, we are using a combined perioperative “anti-stress immune-stimulatory” approach, combining CpG-C use withblockade of CAs and PGs signalling during surgery, aiming to devise multi-factorial anti-metastatic perioperative treatment without adverse effects. Most importantly, we are now conducting several translational studies in preparation for employing this integrated approach in cancer patients in future clinical trials. 

Project | 02
Project | 02
 
Spontaneous regression of micro-metastases following primary tumor excision: A critical role for primary tumor secretome

Numerous case studies have reported spontaneous regression of recognized metastases following primary tumor excision, but underlying mechanisms are elusive, and no animal model of regression of spontaneous metastasis is available to systematically study this phenomenon. We recently presented a model of metastases regression and latency following PT excision, and identified potential underlying mechanisms, using the human MDA-MB-231HM breast cancer line in BALB/c nu/nu mice (yet unpublished). Removal of the PT caused marked regression of the smallest micro-metastases, and in vivo supplementation of tumor secretome diminished this regression, suggesting that PT-secreted factors promote early metastatic growth. We further identified specific mediating factors of these processes, including IL-8, PDGFaa, Serpin E1 (PAI-1), and MIF.  Currently we are attempting to generalize these finding to syngeneic tumor models, to identify mediating secreted factors, and to devise prophylactic approaches aiming at arresting metastatic progression perioperatively based on such insights.  If successful, these studies can suggest novel approaches to control minimal residual disease during and following PT excision.

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