Good news! Cancer is history (soon)! This could be a breakthrough!
"Triple-negative breast cancer (TNBC) is one of the most aggressive and treatment-resistant forms of breast cancer. It grows quickly, spreads early and lacks the hormone receptors that make other breast cancers treatable with targeted therapies. Even when patients initially respond to treatment, the cancer often returns and is more resistant than before.
A new study in Breast Cancer Research points to a promising strategy to overcome the cancer's resistance. Researchers ... have developed an antibody that blocks several of the ways TNBC cells survive, grow and evade the immune system. In early testing, the antibody suppressed primary tumor growth and the spread of cancer to the lungs and reenergized cancer-fighting immune cells. It even killed cancer cells that had stopped responding to chemotherapy. ...
This preclinical study focused on a protein called secreted frizzled-related protein 2 (SFRP2), which acts as a cancer enabler—fueling tumor growth by supporting new blood vessels, blocking cell death and weakening immune cells that should attack the cancer.
The work builds on nearly two decades of research on SFRP2 ...
"My lab first identified the role of SFRP2 in breast cancer in 2008," ...
In this study, the researchers ... tested the effects of a humanized monoclonal antibody—a highly targeted molecule designed to attach to SFRP2 and inhibit its cancer-causing effects.
Reprogramming the cancer's immune environment
... first examined human triple-negative breast tumors. They found that SFRP2 was present not only in the tumor cells themselves but also in nearby immune cells, including tumor-infiltrating lymphocytes as well as macrophages.
"This is the first time anyone has demonstrated that SFRP2 is expressed on tumor-associated macrophages," ...
Macrophages can be broadly categorized into two types: M1 macrophages that activate the immune system to fight cancer and M2 macrophages that suppress immunity to help cancer grow. In TNBC, macrophages usually skew toward the M2 type. But when treated with the SFRP2 antibody, the macrophages released a surge of interferon-gamma, a key immune signal that pushed them toward the tumor-fighting M1 state. In mice whose cancer had already spread, the antibody still induced this favorable M1:M2 ratio, indicating that it could "retrain" the immune system to fight cancer even in advanced disease. ...
The antibody also re-energized cancer-fighting T-cells, which often become exhausted and stop working effectively in TNBC. Once treated with the antibody, nearby T-cells became more active, suggesting that the treatment may strengthen immune responses that are often weakened in cancer and reduce the success of immunotherapy.
A highly targeted approach against cancer
In two models of advanced TNBC, mice treated with the antibody developed far fewer lung tumors than those not treated with the antibody. ...
Not only was the antibody effective, it was highly targeted. When the researchers tracked its movement in the body, they found that it concentrated in tumor tissue but not in healthy organs or normally growing cells. ...
Finally, the team tested whether the antibody could tackle one of the biggest hurdles in cancer treatment: resistance to chemotherapy. Doxorubicin, a standard drug used for TNBC, often works at first, but many tumors eventually stop responding. After creating cancer cells that no longer responded to doxorubicin, the researchers found that the antibody still triggered strong cell death in these hard-to-treat cells. ..."
From the abstract (unfortunately very technical and hard to read for non experts):
"Purpose
We hypothesize that SFRP2 is a promising target for Triple Negative Breast Cancer (TNBC).
Experimental design
1. Multiplex immunohistochemistry (IHC) was performed on human TNBC to identify SFRP2 localization in the tumor microenvironment.
2. Tumor associated macrophages (TAMs) were isolated from E0771.LMB breast tumors. TAMs were treated with hSFRP2 mAb (10 µM) or control (10 µM) for 1 h and analyzed by western blot and qRT-PCR for IFN-ϒ.
3. SFRP2 and IFN-ϒ mRNA expression levels were analyzed from the Cancer Genome Atlas (tCGA) for breast cancer patients using least squares-linear regression analysis.
4. PY8119 or E0771.LMB TNBC cells were injected i.v. into mice, and mice were treated with either IgG1 or hSFRP2 mAb every 3 days. Lung metastases were counted after 4 weeks and analyzed by IHC for M1/M2 ratio.
5. MDA-MB-231 TNBC cells were injected into the mammary fat pad, and when tumors were established, mice were treated with IGg1 or hSFRP2 mAb every 3 days i.v. for 79 days and tumor volumes were compared.
6. Wild-type (WT) MDA-MB-231 and doxorubicin-resistant MDA-MB-231 cells were treated with hSFRP2 mAb and apoptosis was compared.
Results
1) Multiplex IHC on human breast tumors showed that SFRP2 localized to tumor cells (87%), TAMs (90%), and tumor-infiltrating lymphocytes (TILs) (96%) in the microenvironment.
2) TAMs treated with hSFRP2 mAb had an increase in IFN-ϒ mRNA by 2.35 ± 0.08-fold (n = 3, p = 0.02) and protein levels by1.9-fold compared to control.
3). Analysis of 1075 breast cancer patients from TCGA database revealed a significant negative association between SFRP2 mRNA and IFN-ϒ expression (p < 0.0001).
4) hSFRP2 mAb reduced lung metastases in EO771.LMB (n = 15, p < 0.05) and PY8119 (n = 11, p < 0.05) mice with an increase the M1/M2 ratio in lungs (n = 3, p = 0.02).
5) hSFRP2 mAb inhibited MDA-MB-231 growth in vivo by 61% percent (n = 9, p < 0.001).
6) hSFRP2 mAb promoted apoptosis in doxorubicin-resistant cells (n = 6, p < 0.0001).
Conclusions
SFRP2 localizes to tumor, TAMs and TILs in the tumor microenvironment and is negatively associated INF-ƴ in human tumors. hSFRP2 mAb reduces primary and metastatic TNBC growth, increases INF-ƴ from TAMS, boosts the M1/M2 ratio in lung metastases, and induces apoptosis in doxorubicin-resistant cells."
Antibody halts triple-negative breast cancer in preclinical models (original news release)
Fig. 1 TNBC tumor samples from patients and TNBC cell lines express SFRP2 and CD38, while hematopoietic cells express CD38 only.
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