2021 GBM journey ---
Exerpts from Abstract:
*The mechanisms governing therapeutic resistance of the most aggressive and lethal primary brain tumor in adults, glioblastoma, have increasingly focused on tumor stem cells.
*Integrated proteogenomic and metabolomic analyses of glioblastoma tissues and single cells have revealed insights into the complex heterogeneity of glioblastoma and stromal cells, comprising its tumor microenvironment (TME).
An additional factor, which isdriving poor therapy response is the distinct genetic drivers in each patient’s tumor, providing the rationale for a more individualized or personalized approach to treatment.
*CCL5 was not expressed in glioblastoma stem cells, suggesting a need for paracrine activation of CCR5 signaling by the stromal cells.
TME-associated immune cells, such as resident microglia, infiltrating macrophages, T cells, and mesenchymal stem cells, possibly release CCR5 ligands, providing heterologous signaling between stromal and glioblastoma stem cells.
* These “hotlines” of autocrine and paracrine information use similar “molecular hardware” (chemokines, cytokines, growth factors, enzymes, and other signal transmitters) to interconnect complex cellular activities, promoting tumor progression.
Resident and infiltrating immuno-competent cells express a large number of inflammatory mediators supporting GBM aggressiveness and resistance, partially also due to GBM-derived factors that educate them to do so.
___
2.2. Cancer Stem Cells in Glioblastoma
*Moreover, GSCs reportedly transdifferente to pericytes to support GBM angiogenesis and tumor growth [40], thus to some extent also creating their own microenvironment.
Taken together intratumor cellular heterogeneity may be due to GSC cells of different brain cells and diverse dedifferentiation.
Many attempts to develop targeted or tailored therapies for specific mutations or GBM subtypes largely failed due to these complexities and selective inter-GBM molecular cross talk.
* GBMs that evolved from GSCs are the most aggressive brain tumors with an average survival of only 15 months after surgery and chemo-irradiation [1].
* High rates of therapy resistance and GBM recurrence after therapy are due to the GSC plasticity and intercellular heterogeneity resulting from GSC dedifferentiation.
GSC dedifferentiation results from the loss of stemness genes by the progeny of GSCs
2.3. Glioblastoma Therapy
The standard-of-care therapeutic modalities for GBM (including maximally safe surgical resection, irradiation (IR), chemotherapy with alkylating agent temozolomide (TMZ), and frequency electrotherapy of tumor treating fields (TTF) [32] has increased median patient survival from approximately16 months to 20 months after diagnosis.
The high levels of GBM cell outgrowth throughout the brain make surgical resection mostly incomplete and prevent IR from being focused.
Moreover, GSC plasticity, as described above, promotes therapy resistance to a much greater extent than the blood–brain barrier that is mostly compromised in glioblastoma tumors.
Thus, unlike many other cancer types, in which targeted therapies have improved survival substantially, there have not been similar advances in GBM treatment [41].
* The prolongation of TMZ treatment from 6 to 12 cycles extended neither progression-free nor overall survival [44].
* Secondly, the expression of immune checkpoint proteins, which mediate the direct contact between GBM and cytotoxic CD8+ T cells, such as the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) and cytotoxic T-lymphocyte protein 4 (CTLA-4), can be inhibited by targeted antibodies.
Phase II and III clinical trials are currently assessing anti-hPD-1 and anti-CTLA-4 antibody-based drugs in GBM [82] (see Section 5.2).
*Recent studies have shown functional synergy between the DNA damaging agent, doxorubicin, and the CCR5 inhibitor maraviroc [87,88,92,95,99,119]. DNA damage repair pathways also contribute to the therapeutic resistance of GSCs [2], and therefore, maraviroc and leronlimab are good candidates for adjuvant GBM therapy.
* Autocrine and multicellular paracrine CCL5–CCR interactions represent a new node of cross talk that should be considered as a target for eliminating GBM and GSC activation.
Clinical trials have recently opened targeting CCR5 using a humanized monoclonal antibody (leronlimab) for metastatic triple-negative breast cancer (TNBC) NCT03838367 or a small molecule inhibitor maraviroc for metastatic colon cancer (NCT03631407, NCT03274804).
https://pmc.ncbi.nlm.nih.gov/articles/PMC8123...04464-f001
& look @ the funding sources--- the US & EU know of our GBM.
The Slovenian & Dr. Pestells Hungary cancer commission comes to mind.
Yesterday news is 100% in-line with this publication.
Dr. Pestell after re-joining Cytodyn, took some Leronlimab back to a private corner of Bauch lab, & got to work on this hypothesis.
Jan. 2026 submitted Abstract.
3/23/2026 -- public & ties the entirity of the Leronlimab journey, to justifying pre-dosing GBM surgeries.
Nice !!!
Exerpts from Abstract:
*The mechanisms governing therapeutic resistance of the most aggressive and lethal primary brain tumor in adults, glioblastoma, have increasingly focused on tumor stem cells.
*Integrated proteogenomic and metabolomic analyses of glioblastoma tissues and single cells have revealed insights into the complex heterogeneity of glioblastoma and stromal cells, comprising its tumor microenvironment (TME).
An additional factor, which isdriving poor therapy response is the distinct genetic drivers in each patient’s tumor, providing the rationale for a more individualized or personalized approach to treatment.
*CCL5 was not expressed in glioblastoma stem cells, suggesting a need for paracrine activation of CCR5 signaling by the stromal cells.
TME-associated immune cells, such as resident microglia, infiltrating macrophages, T cells, and mesenchymal stem cells, possibly release CCR5 ligands, providing heterologous signaling between stromal and glioblastoma stem cells.
* These “hotlines” of autocrine and paracrine information use similar “molecular hardware” (chemokines, cytokines, growth factors, enzymes, and other signal transmitters) to interconnect complex cellular activities, promoting tumor progression.
Resident and infiltrating immuno-competent cells express a large number of inflammatory mediators supporting GBM aggressiveness and resistance, partially also due to GBM-derived factors that educate them to do so.
___
2.2. Cancer Stem Cells in Glioblastoma
*Moreover, GSCs reportedly transdifferente to pericytes to support GBM angiogenesis and tumor growth [40], thus to some extent also creating their own microenvironment.
Taken together intratumor cellular heterogeneity may be due to GSC cells of different brain cells and diverse dedifferentiation.
Many attempts to develop targeted or tailored therapies for specific mutations or GBM subtypes largely failed due to these complexities and selective inter-GBM molecular cross talk.
* GBMs that evolved from GSCs are the most aggressive brain tumors with an average survival of only 15 months after surgery and chemo-irradiation [1].
* High rates of therapy resistance and GBM recurrence after therapy are due to the GSC plasticity and intercellular heterogeneity resulting from GSC dedifferentiation.
GSC dedifferentiation results from the loss of stemness genes by the progeny of GSCs
2.3. Glioblastoma Therapy
The standard-of-care therapeutic modalities for GBM (including maximally safe surgical resection, irradiation (IR), chemotherapy with alkylating agent temozolomide (TMZ), and frequency electrotherapy of tumor treating fields (TTF) [32] has increased median patient survival from approximately16 months to 20 months after diagnosis.
The high levels of GBM cell outgrowth throughout the brain make surgical resection mostly incomplete and prevent IR from being focused.
Moreover, GSC plasticity, as described above, promotes therapy resistance to a much greater extent than the blood–brain barrier that is mostly compromised in glioblastoma tumors.
Thus, unlike many other cancer types, in which targeted therapies have improved survival substantially, there have not been similar advances in GBM treatment [41].
* The prolongation of TMZ treatment from 6 to 12 cycles extended neither progression-free nor overall survival [44].
* Secondly, the expression of immune checkpoint proteins, which mediate the direct contact between GBM and cytotoxic CD8+ T cells, such as the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) and cytotoxic T-lymphocyte protein 4 (CTLA-4), can be inhibited by targeted antibodies.
Phase II and III clinical trials are currently assessing anti-hPD-1 and anti-CTLA-4 antibody-based drugs in GBM [82] (see Section 5.2).
*Recent studies have shown functional synergy between the DNA damaging agent, doxorubicin, and the CCR5 inhibitor maraviroc [87,88,92,95,99,119]. DNA damage repair pathways also contribute to the therapeutic resistance of GSCs [2], and therefore, maraviroc and leronlimab are good candidates for adjuvant GBM therapy.
* Autocrine and multicellular paracrine CCL5–CCR interactions represent a new node of cross talk that should be considered as a target for eliminating GBM and GSC activation.
Clinical trials have recently opened targeting CCR5 using a humanized monoclonal antibody (leronlimab) for metastatic triple-negative breast cancer (TNBC) NCT03838367 or a small molecule inhibitor maraviroc for metastatic colon cancer (NCT03631407, NCT03274804).
https://pmc.ncbi.nlm.nih.gov/articles/PMC8123...04464-f001
& look @ the funding sources--- the US & EU know of our GBM.
The Slovenian & Dr. Pestells Hungary cancer commission comes to mind.
Yesterday news is 100% in-line with this publication.
Dr. Pestell after re-joining Cytodyn, took some Leronlimab back to a private corner of Bauch lab, & got to work on this hypothesis.
Jan. 2026 submitted Abstract.
3/23/2026 -- public & ties the entirity of the Leronlimab journey, to justifying pre-dosing GBM surgeries.
Nice !!!
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