Ivermectin for Radiation-Linked Cancers

Customizing Specific CSC Protocols

Courtesy of Surviving Cancer, COVID-19 & Disease: The Repurposed Drug Revolution

We all know that ionizing radiation from an atomic bomb dramatically increases cancer risk. Leukemia risk is increased 70-fold in children exposed to an atomic explosion.

In patients exposed to Cancer-Related Radiation Therapy there is a lesser but definite increased risk of developing secondary cancers.

For Sarcoma, the risk of secondary cancer is increased 40-fold at high doses, but still 2-fold at doses less than 2GY. Radiation treatment-related secondary cancers are well documented in cases of Testicular, Hodgkins, and Endometrial Cancers, but what is less known is the general effect of Radiation Therapy on Cancer Stem Cells.

These are the slowly differentiating cells that comprise 1 to 2 % of the tumor mass.

What follows will be a shock to many readers, as AI has unearthed what appears to be unexpected information to most, whether physicians, oncologists, or patients. But allow me to present this in a positive way. This is an opportunity to educate and inform everyone on the best repurposed drug combinations to support radiation treatment.

While borrowing from AI searches, allow me to explain how all of this can help anyone with cancer.

Here is the Radiation Therapy Effect on Cancer Stem Cells, the roots of cancer. These are those microscopic cells capable of spreading and reconstituting the original tumor many times over at distant locations in a completely resistant and mutated form [Refer to the Tree illustration above and notice how radiation to the leaves and branches creates new seedlings that sprout into new trees far away. And these new trees will be radiation resistant].

This suggests that at least one of the reasons for cancer after radiation may be stimulation of cancer stem cells.

However, the key feature here is not merely stimulation of existing CSCs but is the conversion of fast-differentiating cancer cells to slow-growing cancer stem cells, a de-differentiation process whereby new CSC colonies are created.

Radiotherapy remains a cornerstone of cancer treatment, but treatment resistance continues to be a major obstacle for successful outcomes. Traditionally, radioresistance was attributed solely to a small pre-existing population of intrinsic cancer stem cells within tumors. These intrinsic CSCs were thought to survive radiation while the majority of "regular" cancer cells (non-stem cancer cells) would die from treatment. However, Fengsheng Li's team presents compelling evidence that radiation therapy itself can induce the creation of new CSCs from previously non stem cancer cells.

It is true that regrowing an entire bulky tumor from a microscopic colony might take many months or years depending upon the aggressiveness of the cancer. While one might benefit in the short term from the Radiation Therapy’s effect on the visible tumor, the long-term price to pay might be a recurrence or worse.

However, if the specific pathways that the radiation treated were suppressed with repurposed blocking agents from the start of treatment, one could potentially enjoy the benefits of the treatment while minimizing the risk of recurrence.

So, I studied radiation therapy’s CSC effect further. Which pathways are most active in stimulating these CSCs?

A great many CSC growth pathways exist, and my readers should know at least seven by now: WNT, Notch, Hedgehog, P13/AKT, STAT3, JAKSTAT, and NF-kB.

Here are the Top 7 CSC Growth Pathways:

• WNT

• Notch

• Hedgehog

• Nf-KB

• P13K/AKT

• STAT3

• JAK/STAT

Radiation Stimulates Mainly Three CSC Pathways: WNT, Notch & STAT3:

Here are the Top 3 Radiation Activated CSC Pathways:

• WNT

• Notch

• STAT3

Thus, the main drivers in radiation therapy are the WNT, Notch and STAT3. Recall that we know that the blockers of the three key pathways can be gleaned from our prior rankings and supporting PubMed studies.

The Top WNT CSC Blockers:

• Ivermectin

• Curcumin

• Sulforaphane

• Doxycycline

The Top Notch CSC Blockers:

• Curcumin

• Doxycycline

The Top STAT3 CSC Blockers:

• EGCG

• Resveratrol

• Omega 3

Main Radiation CSC Blockers:

• Ivermectin - blocks all three pathways with WNT most.

• Curcumin - blocks all three pathways with Notch most.

Secondary Radiation CSC Blockers

• Doxycycline - blocks two of three pathways

Others Block at Least One CSC Pathway

EGCG, Sulforaphane, Resveratrol, and Omega 3.

The Risk/Benefit Analysis of Radiation Therapy in Stage 4 Cancers:

While Radiation Therapy has many benefits, especially in lymphomas, testicular cancer and many other early-stage tumors, it can be a double-edged sword in advanced disease where it has two adverse effects:

#1. The creation of new CSC populations from non-stem cancer cells.

#2. The activation and stimulation of existing CSC populations within the tumor.

I have no problem with the use of Radiation Therapy in those cancers which may be cured with its use. Some cancers can be cured with radiation therapy alone.

Hodgkin's lymphoma demonstrates exceptional response to radiation therapy. For Stage I and II Hodgkin's disease, radiation therapy achieves impressive 10-year survival rates of approximately 90%. Low-grade Non-Hodgkin's lymphomas also show favorable responses to radiation therapy alone.

And in the middle are other locally advanced cancers which can be cured with a combination of chemotherapy and radiation.

However, with the discovery of Cancer Stem Cells in leukemia in 1994 and the expansion to solid tumors in 2003, the current science is that CSCs pose an increased risk for advanced [Stage 4] cancer relapse following initial treatment.

When we factor in the specific chemotherapy drugs and their unique CSC pathway stimulation effects, we see that a more nuanced approach may be best.

Chemotherapy’s Effect on Cancer Stem Cell Pathway Stimulation:

When we rank certain traditional chemotherapy treatments alongside Radiation Therapy, we find the CSC stimulation problem is substantial.

For example, Paclitaxel and Doxorubicin both highly stimulate CSCs along different pathways. The good news, however, is that one can target those pathways with repurposed blocking agents.

Improving the Odds of Success with Radiation + Chemotherapy:

Target the CSCs with Repurposed Drugs

Strategy: Analyze the Treatment [not just the cancer] to Target the CSCs that will be stimulated with #1. Radiation Therapy and #2. Chemotherapy

#1. Target Radiation Therapy CSCs.

And it would seem essential to provide WNT, Notch, and STAT3 Inhibitors concurrently with any Radiation Treatment, especially if the agents are safe repurposed drugs.

Main Radiation CSC Blockers:

• Ivermectin - blocks all three pathways

• Curcumin - blocks all three pathways

Secondary Radiation CSC Blockers

• Doxycycline - blocks two of three pathways

Others Block at Least One Radiation CSC Pathway

EGCG, Sulforaphane, Resveratrol, Omega 3, and Vitamin D.

#2. Target Chemotherapy CSCs:

Identify the main pathways Doxorubicin stimulates and then find the main repurposed drug blockers on these pathways. We will use Doxorubicin in one of the examples below.

Best Practices: Customize CSC Blockers to Your Specific Treatment:

Indeed, the current PubMed research through multiple studies also strongly advises CSC blockers to be administered concurrently with any radiation therapy for late-stage cancer.

Below I will provide examples of other Radiation + Chemotherapy Protocols and how I arrive at specific Repurposed Drug Protocols to block the stimulating effects of each protocol.

Example #1 - Designing a Repurposed Drug Combination against a Typical Colon Cancer Treatment Protocol

Assuming Specific Course of No Radiation Treatment but Chemotherapy of 5FU, Leucovorin, and Oxaliplatin [FOLFOX Protocol]:

A. No radiation treatment so no counter-radiation repurposed drugs needed

B. Here is the analysis on CSC pathways stimulated by the FOLFOX protocol:

The three key pathways stimulated by FOLFOX are:

• WNT: Blocked by Ivermectin, Curcumin, Sulforaphane, Doxycycline

• P13/AKT: Blocked by Metformin, Ivermectin, Resveratrol

• Notch: Blocked by Curcumin, Doxycycline

Customized Protocol Against FOLFOX:

#1. Ivermectin

#2. Curcumin

#3. Doxycycline/ Vitamin C (oral)

#4. Metformin

#5. Sulforaphane

#6. Resveratrol

Cancer Stem Cell Pathway Activation by FOLFOX Regimen: A Comprehensive Analysis

The FOLFOX regimen, consisting of 5-Fluorouracil (5-FU), oxaliplatin, and leucovorin, remains a cornerstone treatment for colorectal cancer (CRC).

• However, cancer stem cells (CSCs) contribute significantly to treatment resistance and disease recurrence.

• Here we analyze the differential activation of key CSC signaling pathways by FOLFOX treatment and rank their relative importance in mediating resistance.

Pathway Activation Ranking and Mechanism Analysis

Cancer stem cell pathways play critical roles in maintaining stemness properties, self-renewal capacity, and chemoresistance. Based on the available evidence, these pathways are differentially activated following FOLFOX treatment.

WNT/β-catenin Pathway: Primary Mediator of FOLFOX Resistance

The WNT/β-catenin pathway emerges as the most prominently activated pathway in response to FOLFOX treatment.

• 5-FU, a key component of FOLFOX, significantly upregulates WNT signaling through p53-mediated WNT3 transcription. This activation leads to enrichment of CSCs in residual tumors following treatment, directly contributing to recurrence.

• Studies with patient-derived tumor organoids and cells demonstrate that FOLFOX-induced CD44v6 expression maintains stemness traits by promoting several antiapoptotic and stemness genes, including FZD1 (a WNT receptor).

• The critical role of this pathway is further supported by evidence that cancer stemness inhibitors targeting β-catenin show promising results in advanced colorectal cancer patients previously treated with chemotherapy.

PI3K/AKT Pathway: Key Mediator of Survival and Self-Renewal

• The PI3K/AKT pathway ranks second in importance for FOLFOX-induced CSC activation. Increased phosphorylation of AKT1/mTOR/4EBP1 is consistently observed in FOLFOX-resistant CRC cells.

• This pathway is directly linked to multiple CSC-associated characteristics, including therapy resistance, self-renewal capacity, and tumorigenic potential.

• Significant evidence shows that PI3K/AKT signaling is substantially higher in colorectal CSCs compared to bulk cancer cells, and inhibition of this pathway can restore sensitivity to FOLFOX treatment.

• PIK3CA mutations frequently observed in CRC patients confer resistance to FOLFOX through enhanced PI3K/AKT signaling, further validating this pathway's critical role in treatment resistance.

Notch Pathway: Mediator of Stemness Maintenance

The Notch pathway ranks third in significance for FOLFOX-induced CSC activation.

• Enhanced Notch signaling is frequently observed in CRC cells resistant to 5-FU or oxaliplatin, particularly in spheroid cultures enriched for CD133+ and CD44+ stem cells.

• JAG1/NOTCH1/HES1 signaling plays an essential role in maintaining CSC viability by inhibiting apoptosis and preventing cell cycle arrest.

• Notch pathway activation following chemotherapy contributes to differentiation blockade and self-renewal of CSCs.

• Interestingly, the unbalanced distribution of NOTCH1 signaling promotes asymmetric division of CSC populations, establishing a heterogeneous tumor environment that contributes to treatment resistance.

Example #2: Breast Cancer Treatment using AC Protocol + Radiation:

AC as a Continuing Standard of Care

The AC protocol and its variants have remained standard treatments for breast cancer for approximately 30-35 years since the early 1990s. While the landscape of breast cancer treatment has evolved considerably, AC-based regimens remain important options in current treatment protocols.

AC combines Doxorubicin with Cyclophosphamide.

The best time to ask which repurposed drugs best counter the CSC stimulation effects of the AC protocol is at the beginning of treatment. This is the best time to design a targeted protocol of repurposed CSC blockers to improve survival.

Here is another example of how to design a repurposed drug protocol that counters the effect of treatment enhancement of the Radiation and Chemotherapy stimulation of Cancer Stem Cells.

A. EBRT Stimulates WNT, Notch, and STAT3.

• Top 3 repurposed drugs against EBRT: Ivermectin, Curcumin, and Doxycycline.

B. AC protocol includes Doxorubicin & Cyclophosphamide

Identify Repurposed Agents that Inhibit NF-KB, STAT3 and Notch Pathways:

Top 3 repurposed drugs against the main treatment stimulated CSC pathways:

• Notch: Curcumin, Doxycycline

• Nf-KB: Curcumin, Resveratrol, EGCG

• STAT3: EGCG, Resveratrol, Omega 3

The Main Blockers of Notch/Nf-KB/STAT3 CSC pathways [Doxorubicin + Cyclophosphamide stimulated] are:

• Curcumin

• Resveratrol

• EGCG

The Main EBRT(Radiation Rx) Blockers are:

• Ivermectin

• Curcumin

• Doxycycline

Doxorubicin + Cyclophosphamide stimulate CSCs. Thus, the Best Chemo Blockers are:

• Curcumin

• Resveratrol

• EGCG

Summary Breast Cancer Protocol [Customized Against EBRT + AC] would include at the least:

• #1. Ivermectin

• #2. Curcumin

• #3. Doxycycline/ Vitamin C (oral)

• #4. Resveratrol

• #5. EGCG

Next, we will review additional Chemo + Radiation Protocols against other common cancers. Then we will derive repurposed drug protocols designed to block treatment-associated CSC pathways.

And if your specific protocol [chemo + radiation] is not included, we will accept requests to use AI to address the main CSC pathways affected by your treatment protocol and will propose the Top 5 to 10 Repurposed Drugs that can inhibit these stimulating effects. These will be added below.

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