Novel SM-88 Therapy Has Potential Efficacy in Metastatic Breast Cancer

MedicalResearch.com Interview with:

Dr. Giuseppe Del Priore, MD, MPH Chief Medical Officer of Tyme Inc. 

Dr. Del Priore

Dr. Giuseppe Del Priore, MD, MPH
Chief Medical Officer of Tyme Inc.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Metastatic breast cancer, sometimes also called “stage IV” or “advanced breast cancer,” is the most extensive stage of breast cancer. It is an invasive cancer that has spread to other parts of the body, most often bones, lungs, liver, and brain. The current standard of care for metastatic breast cancer is systemic drug therapies, such as hormone therapy, chemotherapy, targeted drugs or a combination of these.  Because they reach every cell in the body, they have side effects that can worsen the patient’s quality of life. Existing treatments cannot cure metastatic breast cancer and are palliative in intent. This presents a great unmet need and challenge in treating patients with metastatic breast cancer.

SM-88 is a novel relatively non-toxic combination therapy that harnesses cancer’s unique cell metabolism and oxidative stress to selectively drive cancer cell death. Earlier studies with SM-88 therapy demonstrated its potential efficacy in breast and other metastatic cancers. In this current report, we assessed the efficacy of SM-88 in patients with metastatic breast cancer from the first in human “Phase 1” and compassionate use programs from 2012 to 2017. Data demonstrated the potential efficacy of SM-88 in metastatic breast cancer with favorable safety and quality of life profiles. In addition, there were no indications of cross-resistance based on hormone profile, previous treatments or metastatic site. This is an extremely important finding since most cancer deaths are due to resistance to subsequent therapies.  As predicted by the SM-88 mechanism of action, we could not detect this problem with SM-88 use.

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Phase I Study Successfully Targets Metastatic Kidney Cancer

MedicalResearch.com Interview with:

Kevin D. Courtney, M.D., Ph.D.  Assistant Professor UT Southwestern Medical Cente

Dr. Courtney

Kevin D. Courtney, M.D., Ph.D. 
Assistant Professor
UT Southwestern Medical Center

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer. Metastatic ccRCC does not respond to traditional chemotherapy.

Current standard treatments for metastatic ccRCC include drugs called vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) that block the growth of new blood vessels that feed the cancer, as well as drugs that inhibit an enzyme called mTOR that is involved in ccRCC growth and immune therapies that rev up the body’s immune response to try to fight the cancer. Each of these treatments can have significant side effects for patients that can make them difficult to tolerate.

Metastatic ccRCC is largely incurable, and we need novel and better-tolerated treatments. A central driver of ccRCC is a protein called hypoxia inducible factor 2alpha (HIF-2alpha). This protein has been very difficult to try to target with a drug. This study is the first to test a drug that targets HIF-2alpha in patients with metastatic ccRCC. The study results showed that the HIF-2alpha inhibitor, PT2385 (Peloton Therapeutics) was active in fighting metastatic ccRCC and was well-tolerated.

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Zoledronic Acid Cost-Effective In Preventing Skeletal Events in Patients With Bone Metatstases

MedicalResearch.com Interview with:

Dr-Charles L Shapiro.jpg

Dr. Shapiro

Charles L.Shapiro MD
Professor of Medicine
Director of Translational Breast Cancer Research
Director of Cancer Survivorship
Division of Hematology/Oncology
Tisch Cancer Institute
New York, NY

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The new 2017 ASCO guidelines for the use bone-modifying in individuals with bone metastases recently endorsed every 3-month zoledronic, because of high level evidence from three randomized trials, including our trial (published in Jama in Jan 2017, first author Himelstein et al) that giving zoledronic acid every 3-months was non-inferior to the standard of monthly zoledronic. The guidelines also concluded that there was not one preferred bone modifying agent of the other, despite the fact the comparing monthly zoledronic to monthly denosumab in women with bone metastases, denosumab delayed the time to first skeletal-related event (pathological fractures, necessity for radiation or surgery, and spinal cord compression) and subsequent events by 23% (or in absolute terms about 3 months) . Zoledronic acid became generic in 2013, whereas monthly denosumab is still patented until 2022-25.

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Doubt Cast on Traditional Pattern of Cancer Metastases

MedicalResearch.com Interview with:
Benjamin Weixler, MD
Department of Surgery
University Hospital Basel, Basel, Switzerland and
Leiden University Medical Center, Leiden, the Netherlands 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: For most patients with lymph node negative colon cancer (stage I and II) surgery is regarded to be the curative treatment. Despite the curative attempt up to thirty percent of these patients will develop disease recurrence, most likely due to missed micro-metastatic disease at initial tumor staging. Pathological standard processing with hematoxylin and eosin (H&E) entails a considerable risk of missing micro-metastatic deposits in the lymph nodes. Mounting evidence indicates that micro-metastatic tumor deposits in the lymph nodes as well as in the bone marrow might be associated with an increased risk of disease recurrence and death in node negative patients. With our study we wanted to examine the correlation between the occurrence of micro-metastatic deposits in the lymph nodes and the bone marrow as well as their prognostic significance.

As a main finding, the study provides compelling evidence that tumor cell dissemination to the lymph nodes and to the bone marrow are independent events in patients with colon cancer. Most importantly did the study demonstrate that micro-metastatic deposits in the lymph nodes as well as in the bone marrow are independent negative prognostic factors regarding  disease-free and overall survival. The combined occurrence is associated with significantly worse prognosis compared to either one of them.

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Bisphosphonates Can Be Reduced In Second Year of Breast Cancer Metastases

MedicalResearch.com Interview with:

Gabriel N. Hortobagyi, MD, FACP, FASCO Professor, Department of Breast Medical Oncology Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX 77230-1439

Dr. Gabriel Hortobagyi

Gabriel N. Hortobagyi, MD, FACP, FASCO
Professor, Department of Breast Medical Oncology
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX 77230-1439 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Bisphosphonates have been commercially available for several decades as supportive care for patients with bone metastases. They reduce the frequency and severity of bone-related complications. While the optimal dose and short-term scheduling of zoledronic acid (and previously, pamidronate) have been determined, there has been no research to determine how long these drugs need to be maintained nor the optimal dose and schedule beyond the first year of therapy. These questions are particularly important for this family of drugs, since they are incorporated into bone and not excreted from the body for many years.

We set out to determine whether a reduction in the frequency of administration of zoledronic acid (every 12 weeks) was able to maintain the therapeutic efficacy of this intervention when compared to the “standard” schedule of administration (every 4 weeks). It was a prospective, randomized, non-inferiority trial that recruited patients with metastatic breast cancer with bone metastases and who had previously received 9 or more doses of zoledronic acid or pamidronate. The primary endpoint was the proportion of patients with one or more skeletal-related events. Four hundred and sixteen patients were randomized in a 1:1 ratio. The two groups were comparable at baseline. After the first year of follow-up, there was no statistically significant difference in SRE rate between the two arms, confirming the non-inferiority fo the every-12-week schedule of zoledronic acid.

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Bisphosphonates For Bone Metastases May Be Given Less Frequently

MedicalResearch.com Interview with:

Charles L. Shapiro, MD Professor of Medicine Co-Director of Dubin Breast Center Director of Translational Breast Cancer Research Director of Cancer Survivorship, Tisch Cancer Institute Mount Sinai Health System Division of Hematology / Medical Oncology: Tisch Cancer Institute New York, NY 10029

Dr. Charles Shapiro

Charles L. Shapiro, MD
Professor of Medicine
Co-Director of Dubin Breast Center
Director of Translational Breast Cancer Research
Director of Cancer Survivorship, Tisch Cancer Institute
Mount Sinai Health System
Division of Hematology / Medical Oncology: Tisch Cancer Institute
New York, NY 10029

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Metastases to bone are frequent in many cancers and cause pain, pathological fractures, necessitate surgical and/or radiation treatments, cause spinal chord compression that can lead to paralysis, and significantly increase health care costs.

Zoledronic acid, a bisphosphonate that inhibits bone resorption, is used in standard practice because it reduces the risks skeletal-related events including cancer-related pathological fractures, the need for surgery and/or radiation to bone metastases, and spinal chord compression in patients with breast cancer, prostate cancer and multiple myeloma.

However, the optimal dosing interval for zoledronic acid is unknown and based on prior studies and empiricism it is administered monthly along with anti-cancer treatments.

In this trial, over 1800 breast cancer, prostate cancer and multiple myeloma patients with bone metastases were randomized to the standard dosing interval of monthly zoledronic acid versus every 3-months zoledronic acid for a duration of two years.

The results overall, and in each specific disease site, show that giving zoledronic acid once every 3-months as opposed to monthly did not result in any increase in skeletal-related
events.

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Incidence of Metastatic Prostate Cancer at Diagnosis Rises in US

MedicalResearch.com Interview with:

Dr. Jim C. Hu MD MPH Professor of Urology Weill Cornell Medicine

Dr. Jim Hu

Dr. Jim C. Hu MD MPH
Professor of Urology
Weill Cornell Medicine

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The most significant finding from our population based study is that after years of decline following the introduction of PSA screening, we see a rise in the incidence of metastatic prostate cancer at diagnosis among men aged 75 years and older. This is concerning in light of recent criticisms and guidelines against PSA testing. For instance, in 2008, the US Preventative Services Task Force recommended against PSA testing in this age group, and in our study, we see the incidence of metastasis at diagnosis rising in 2012 and 2013.

This is significant because there is no cure for men with metastatic prostate cancer of their disease. The traditional argument against PSA screening is that it leads to over-diagnosis and over-treatment of prostate cancer. However, we currently do not have a better test for diagnosing prostate cancers before it has spread beyond the prostate and metastasized. Remarkably, when Ben Stiller shared his personal use of PSA testing in his mid to late 40’s and how this led to a detection of intermediate risk prostate cancer that led him to surgery and cure, others criticized him for sharing his story.

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IL-33 May Be First Stand Alone Biomarker of Prostate Cancer Recurrence

MedicalResearch.com Interview with:
Iryna Saranchova MD
PhD candidate
Michael Smith Laboratories
Vancouver, BC

MedicalResearch.com: What is the background for this study?

• The immune system is efficient at identifying and halting the tumour emergence at early stages. However, when metastatic (sufficient to cause death) tumour appears, the immune system is no longer able to recognize the cancer cells and control their growth and spread.
• Recent studies of solid cancers have shown considerable heterogeneity between different tumour types and several lines of evidence suggest that tumours are not only heterogeneous, but they constantly evolve during the disease progression and this often hampers the existing treatment methods.
• It means that it is important to consider each patient’s mutational changes accumulated over time in antecedent primary, metastatic lesions and/or local recurrences. This approach will help to understand the mechanism of tumour development, create a background for specific treatment modality and prevent therapeutic failure with consequent systemic relapse of the disease
• Therefore, in our project we were aiming to find possible immune markers of tumour transition from the primary stage to its metastatic form. For this purpose, we selected a special study model: two pairs of separate mouse tumour cell lines, where metastatic cells arose from the initial primary tumour.

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Scaffold Can Potentially Deliver Therapeutic miRNA To Decrease Breast Cancer Metastases

MedicalResearch.com Interview with:

Natalie Artzi PhD principal research scientist MIT's Institute for Medical Engineering and Science (IMES) and Assistant professor of medicine Brigham and Women's Hospital And co-authors: Avital Gilam, João Conde, Daphna Weissglas-Volkov, Nuria Oliva Eitan Friedman, Noam Shomron

Dr. Natalie Artzi

Natalie Artzi PhD
principal research scientist
MIT’s Institute for Medical Engineering and Science and
Assistant professor of medicine
Brigham and Women’s Hospital
With co-authors:
Avital Gilam, João Conde, Daphna Weissglas-Volkov, Nuria Oliva, Eitan Friedman, Noam Shomron

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Metastases are the primary cause for mortality in breast cancer, the most common cancer in women regardless of ethnicity. Recent studies show that germline sequence variants, such as single-nucleotide polymorphisms (SNPs) in miRNA-binding sites, can disrupt the downregulation by miRNAs, with a profound effect on gene expression levels and consequentially on the phenotype, including increased risk for cancer.

In the current study, we aimed to determine the potential effect of SNPs within miRNA-binding sites on metastatic breast cancer progression and their potential use as suppression targets to prevent metastasis.

Our collaborators at Tel-Aviv Universityin a research led by Dr. Noam Shomron found that the SNP, rs1071738, located in a target site for miR-96 and miR-182 on the 3’-UTR of the PALLD gene, encodes the Palladin actin-associated protein, which is a documented player in breast cancer motility. In vitro experiments revealed a functional downregulation of Palladin levels by miR-96 and miR-182, which subsequently reduces migration and invasion abilities of breast cancer cells.

My lab then showed in an in vivo experiment that the use of nanoparticles embedded in a hydrogel scaffold as a miRNA delivery vehicle enables an efficient and specific delivery of miR-96/miR-182 directly to breast tumours, which results in marked reduction of breast cancer metastasis. We then proceeded to study the effect of combination therapy in which we will use a chemotherapy drug to shrink the primary tumor and the miRNAs to prevent metastasis. The intercalation of a chemotherapy drug, cisplatin, to the miR-conjugated nanoparticles further improved the effect, leading to significant reduction in both primary tumour growth and metastasis.

Our study highlights the therapeutic potential of miRNAs, and specifically miR-96 and miR-182, and support the importance of Palladin regulation in breast cancer metastasis.

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Lymph Node Cancer Metastases Do Not Require Growth of New Blood Vessels

Timothy P. Padera, PhD Edwin L. Steele Laboratories Department of Radiation Oncology MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts 02114MedicalResearch.com Interview with:
Timothy P. Padera, PhD
Edwin L. Steele Laboratories
Department of Radiation Oncology
MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School
Boston, Massachusetts 02114

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Padera: Systemic therapy benefits cancer patients with lymph node metastases; however all phase III clinical trials to date of antiangiogenic therapy have failed in the adjuvant setting. We have previously reported the lack of efficacy of antiangiogenic therapies in pre-clinical models of spontaneous lymphatic metastasis, however there were no mechanistic data to explain these observations. Here, we developed a novel chronic lymph node window model to facilitate new discoveries in the mechanisms of growth and spread of lymph node metastases. Our new data provide pre-clinical evidence along with supporting clinical evidence that angiogenesis does not occur in the growth of metastatic lesions in the lymph node. These results reveal a mechanism of treatment resistance to antiangiogenic therapy in adjuvant setting, particularly those involving lymph node metastases.

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Understanding Leader Cells In Cell Migration

MedicalResearch.com Interview with:
Dr. Pak Kin Wong Ph.D.
Aerospace& Mechanical Engineering Department Biomedical Engineering and Bio5 Institute
The University of Arizona

Medical Research: What is the background for this study? What are the main findings?

Response: Collective cell migration is central to various (patho)physiological processes, such as tissue development, regeneration, and cancer metastasis. At the onset of the process, a subset of cells acquires distinct leader cell phenotypes in the initially homogeneous population and leads the migration. However, how leader cells are initiated among the initial homogeneous population and how leader cell density is regulated during collective migration remain unknown. In this study, we demonstrate the formation of leader cells is regulated dynamically by Dll4 signaling through Notch1 and cellular stress near the leading edge. Our finding provides a molecular basis for the stochastic emergence of leader cells, a process originally considered random.

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Pathways to Breast Cancer Bone Metastases Identified

Dr. Xiang (Shawn) Zhang PhD Assistant Professor Department of Molecular and Cellular Biology Lester and Sue Smith Breast Center Baylor College of Medicine Houston, TexasMedicalResearch.com Interview with:
Dr. Xiang (Shawn) Zhang PhD

Assistant Professor
Department of Molecular and Cellular Biology
Lester and Sue Smith Breast Center
Baylor College of Medicine Houston, Texas

 

Medical Research: What is the background for this study? What are the main findings?

Response: Bone metastases present a major clinical problem for oncologists. They are very painful and unpleasant due to the ability of metastatic cells to dissolve bones, and if they spread to the spine or vertebrate bone they  the spinal cord compression could cause paralysis. There is a gap in our knowledge about bone metastasis in breast cancer. We know a lot about when they are fully established and already dissolving the bone, but little about what happens early on, right after the cancer cells get there but before they start the bone-dissolving process.

In the study, we revealed that in the early stages, when there are only a few cancer cells, these cells tend to locate themselves in a microenvironment that is enriched in bone making cells called osteoblasts whose normal job is to help make new bones. The cancer cells appear to be surrounded by these bone-making cells before they acquire the ability to dissolve bones.

We also uncovered the pathway that gets activated when the cancer cells lodge into the bone-making cells, and helps them progress to more malignant metastases. The action is mediated by a class of proteins that helps bind the cancer cells to the bone tissue called heterotypic adherens junctions (hAJs) involving the adherens proteins E-cadherin (cancer-derived) and N-cadherin (bone-promoting). This then activates the mTOR pathway in cancer cells, which drives the progression from single cells to metastases.

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Castration-Resistant Prostate Cancer: Serum Biomarkers of Bone Metabolism

Primo N. Lara, Jr, MD, Professor of Medicine, University of California Davis School of Medicine Associate Director for Translational Research UC Davis Comprehensive Cancer Center Sacramento, CA 95817MedicalResearch.com Interview with:
Primo N. Lara, Jr, MD,
Professor of Medicine, University of California Davis School of Medicine
Associate Director for Translational Research
UC Davis Comprehensive Cancer Center
Sacramento, CA 95817

MedicalResearch.com: What are the main findings of the study:

Dr. Lara:  “We found that blood markers of bone turnover can be used to predict outcomes in men with advanced prostate cancer with spread to bone. We also found that a small proportion of men could be predicted to benefit from an investigational drug based on these same markers.”
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Lung Cancer: Calcineurin Pathway Helps Enable Metastases

Sandra Ryeom, PhD, Assistant professor of Cancer Biology, Perelman School of Medicine, University of Pennsylvania
MedicalResearch.com Interview with:
Sandra Ryeom, PhD,
Assistant professor of Cancer Biology,
Perelman School of Medicine, University of Pennsylvania


MedicalResearch.com: What are the main findings of the study?

Answer: We identified an important pathway (calcineurin-NFAT-Angiopoeitin2) in the vasculature of early metastatic lung lesions that is critical for promoting lung metastases.

MedicalResearch.com: Were any of the findings unexpected?

Answer: Since there is limited understanding of regulation of tumor angiogenesis at metastatic sites, identification of the calcineurin pathway and a newly identified target of calcineurin-NFAT signaling  was all unexpected.
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Eradicating disseminated tumors, even in brain, by injecting specific antibodies

MedicalResearch.com eInterview with Ronald Levy, M.D.
Professor and Chief Division of Oncology
Stanford University, 269 Campus Drive
Stanford, California 94305, USA

MedicalResearch.com: What are the main findings of the study?

Dr. Levy: Injection of antibodies that deplete Treg cells directly into a tumor can evoke an immune response that cures  the animal of distant, untreated tumors.

This effect eliminates cancer even in the brain.

The dose of antibodies locally injected can be as low as 1/100 the dose used for systemic injection and therefore should avoid the usual autoimmune side effects of these antibodies.
The antibodies used are directed against CTLA4 and OX40 antigens.

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Predicting Aggresive Metastasis-Prone Lung Cancer by Identification of Abnormally Activated Genes

MedicalResearch.com Authors’ Interview: Sophie Rousseaux and Saadi Khochbin

INSERM, U823; Université Joseph Fourier, Grenoble 1; Institut Albert Bonniot, Grenoble F-38700, France.

MedicalResearch.com: What are the main findings of the study?

Answer: We first discovered that all cancer cells lose the ability to maintain gene silencing and therefore activate genes that should normally remain silent. Although present in all cells, some genes are normally expressed (or “active”) only in one cell type. For example, normal lung cells do not express genes that are only active in germ cells (i. e., cells that will become spermatozoa), but lung cancerous cells activate some of these germ cells-specific genes. In this work we designed a specific approach to detect these aberrant gene expressions and found that they occur in all cancers of all origins.

We then decided to exploit this phenomenon to help the detection of cancers and predict their evolution. For this purpose, we chose to focus on lung cancer to establish “a proof of principle”.

We found that, among all the genes wrongly expressed in the tumour cells, the activation of 26 of them enabled us to identify the most aggressive lung cancers. Compared with the existing information currently available for doctors (i.e.; tumour size, its pathological subtype…), our approach brings much more precision in predicting the evolution of the tumours and the prognosis of the patients.
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How metastasizing cancer cells enter organs

It is not primary tumors that are responsible for the majority of cancer deaths, but rather their metastases. Physiologists and neuropathologists from the University of Zurich have now identified the origin of metastasis formation, thereby becoming the first to reveal the pathway of metastasizing intestinal cancer cells out of the blood stream. The results allow new approaches in the development of cancer therapies.

It is not primary tumors that are responsible for the majority of cancer deaths, but rather their metastases. Physiologists and neuropathologists from the University of Zurich have now identified the origin of metastasis formation, thereby becoming the first to reveal the pathway of metastasizing intestinal cancer cells out of the blood stream. The results allow new approaches in the development of cancer therapies.

Every year, over seven million people die of cancer worldwide. Thanks to more effective therapy and better early detection, primary tumors are only responsible for ten percent of cancer deaths in industrial nations. Nowadays, the vast majority die from the consequences of metastasis, namely secondary tumors. These develop from metastases of the primary tumor by spreading via the patient’s bloodstream. Until now, the actual reason for the metastatic spread in certain organs was unknown, it being unclear as to how the secondary cells were able to enter the tissue of other organs from the bloodstream.

Now, a European team headed by physiologists and neuropathologists from the University of Zurich have identified the mechanism that helps metastasizing intestinal cancer cells to infiltrate the organs from the blood vessels. Lubor Borsig and Mathias Heikenwalder’s team demonstrate that cancer cells manipulate specific “doorman receptors” on the endothelium of the blood vessels.

Tumor cells manipulate blood-vessel doorman

Chemokines (intercellular messengers) play a key role in the immune system: They can summon white blood cells directly for immune defense. Tumor cells are also capable of producing chemokines and mobilizing the body’s own special immune cells, monocytes. Consequently, elevated levels of the tumor’s own chemokine CCL2 are characteristic of metastasizing breast, prostate and bowel cancer. Until now, high CCL2 values were primarily taken as an indication of strong tumor growth and a poor prognosis for the disease. Based on in-vivo and in-vitro experiments on lab mice, Borsig and Heikenwälder show that CCL2 is far more than an indicator of the cancer’s aggressiveness. “CCL2 activates a doorman receptor and enables cancer cell to leave the blood circulation and metastasize in other organs,” explains Borsig. The role of the doorman detected on the endothelium for the first time and referred to as CCR2 in a healthy organism is not known. Borsig suspects that the doorman modulates the permeability of the blood vessels during the body’s immune response.

New approach for drug development

“The mechanism discovered will yield a completely new approach for the development of drugs to combat metastasis in breast, prostate and bowel cancer,” Borsig is convinced. Suppressing the tumor’s chemokine expression or blocking the doorman for the tumor chemokine to inhibit any more cancer cells from entering healthy tissue from the bloodstream is conceivable. “If we can succeed in preventing the cancer cells from leaving the bloodstream, the metastasis can be fought directly at the source,” concludes Borsig.

Tumor Cell

This is an electron microscopy from a tumor cell that is on the way to extravasate through an alveolar endothelium blood capillaries – the tumor cell is depicted in blue green, the endothelial cell in purple red. The protrusion of the tumor cell are seen that form their way through the endothelial cell.