Targeting Cancer Stem Cells in Metastatic Colon Cancer with PRI-724

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• Cancer Stem Cell Challenge
• PRI-724 Mechanism
• Clinical Trial Results
• WNT Pathway Importance
• Future Treatment Paradigm
• Full Transcript

Cancer Stem Cell Challenge in Colon Cancer Treatment

Dr. Heinz-Josef Lenz, MD, describes the fundamental reason chemotherapy ultimately fails in metastatic stage 4 colon cancer. He uses a powerful analogy of a tree to explain the problem. Chemotherapy can remove the "leaves" and surgery can cut the "branches" of the tumor, but the "roots" remain. These roots are the cancer stem cells, also known as tumor-initiating cells.

These colon cancer stem cells are highly resistant to all current chemotherapy treatments. They are responsible for tumor regeneration and recurrence, leading to declining response rates with each subsequent line of therapy. Dr. Heinz-Josef Lenz, MD, emphasizes that a new strategy is needed to target these resilient cells directly to achieve a cure.

PRI-724 Mechanism: Differentiating to Kill

The innovative approach with the medication PRI-724 is not to kill cancer stem cells outright but to force them to change. Dr. Heinz-Josef Lenz, MD, explains that these cells cannot be killed in their stem-like state. Instead, PRI-724 works by stimulating them to differentiate into more mature, non-stem cell types.

This differentiation process is the key. Once the colon cancer stem cells have been transformed into regular cancer cells, they lose their protective resistance. These now-vulnerable cells can then be effectively eliminated by conventional chemotherapy, effectively uprooting the cancer and preventing its return.

Clinical Trial Results and Monitoring

Dr. Heinz-Josef Lenz, MD, was part of the team that developed PRI-724 and took it into the clinic for the first time in humans. The preclinical data was promising, showing the medication's ability to eliminate colon cancer stem cells in laboratory models. This success led to a first-in-human, proof-of-principle clinical trial.

To monitor the drug's efficacy in patients, the team used circulating tumor cells. By tracking specific cancer stem cell markers on these cells, they could gather evidence that PRI-724 was working as intended at the molecular level, providing crucial early data on its biological activity.

WNT Pathway Importance in Colon Cancer

PRI-724 is a targeted therapy that inhibits the WNT signaling pathway. Dr. Heinz-Josef Lenz, MD, notes that this pathway is genetically altered in over 95% of all colon cancers, making it a prime target for treatment. The WNT pathway is one of the first activated in human embryonic development, controlling both cell proliferation and differentiation.

The challenge in drug development has been to inhibit only the proliferation arm of the pathway while stimulating the differentiation arm. A blanket inhibition of the entire WNT pathway would be too toxic. PRI-724 represents a step towards this selective targeting, focusing on the specific interactions that allow cancer stem cells to thrive.

Future Treatment Paradigm for Metastatic Disease

Dr. Heinz-Josef Lenz, MD, envisions a new future for treating stage 4 metastatic colon cancer. This paradigm involves combining a stem cell-differentiating agent like PRI-724 with traditional chemotherapy. This one-two punch strategy first exposes the root of the cancer and then destroys it.

This approach is validated in other cancers, such as acute promyelocytic leukemia, where retinoic acid is used to differentiate cancer cells before they are killed. Dr. Lenz believes that targeting colon cancer stem cells through the WNT pathway is the correct strategy to ultimately achieve cures in advanced colorectal cancer patients.

Full Transcript

The full interview transcript between Dr. Anton Titov, MD, and Dr. Heinz-Josef Lenz, MD, provides a detailed account of the discussion on cancer stem cells and the development of PRI-724. Dr. Lenz elaborates on his tree analogy, the mechanism of action of the new drug, and the results from early clinical trials. The conversation covers the critical importance of the WNT pathway in colon cancer biology and the future potential of this targeted approach to change outcomes for patients with metastatic disease.

Full Transcript

Cancer stem cells are responsible for failure of metastatic stage 4 colon cancer treatment. We developed a new WNT pathway inhibitor medication, PRI-724. We used it to treat colon cancer in humans for the first time. We can kill colon cancer stem cells with chemotherapy.

Colon cancer stem cells treatment: PRI-724 chemotherapy. Colorectal cancer stem cells are known as tumor initiating cells. Leading German-American colorectal cancer oncologist discusses colon cancer stem cells (tumor initiating cells). Chemotherapy eventually fails because colorectal cancer stem cells regenerate and escape targeted chemotherapy treatment.

New chemotherapy medication PRI-724 works to inhibit proliferation part of WNT signaling pathway. Cancer stem cells have to be differentiated and then killed by chemotherapy to unroot cancer completely. Treatment of colorectal cancer by stem cell differentiating medications and chemotherapy will succeed to cure more advanced colorectal cancer patients.

Colorectal cancer targeted stem cell chemotherapy options. Advanced stage 4 colon cancer stem cell treatment by targeted chemotherapy. Medical second opinion confirms colorectal cancer diagnosis at genetic level. Medical second opinion also confirms colon cancer cure is possible in metastatic colon cancer.

Best precision medicine stem cell-targeting treatment for advanced stage 4 colon cancer by PRI-724. Medical second opinion helps to select a personalized medicine targeted stem cell treatment for stage 4 colorectal cancer with liver or lung metastases. Get medical second opinion on advanced colorectal cancer. Be confident that your precision medicine treatment is the best.

Best colorectal cancer treatment by new WNT inhibitor PRI-724 to differentiate tumor initiating cells of colorectal cancer. Video interview with leading expert in metastatic colorectal cancer treatment from California. Colon cancer stem cell treatment: PRI-724 to treat colorectal cancer.

Dr. Anton Titov, MD: You have developed a metastatic colon cancer treatment medication that is in clinical trials now. This colon cancer therapy is called PRI-724. It's a very exciting colorectal cancer therapy medication that targets a particular molecular pathway, the WNT and beta-catenin. You worked with Dr. Michael Kahn in the Comprehensive Cancer Center. You developed a stage 4 colon cancer treatment medication.

Can you tell us about this colon cancer medication? What this new colon cancer therapy might bring to the patients in the future?

Dr. Heinz-Josef Lenz, MD: It's very important to know that we cannot cure colon cancer with chemotherapy alone. Why is that? I usually use the example of a tree. This analogy helps to understand why our chemotherapy ultimately fails. It helps to understand why we need in patients with stage 4 colorectal cancer liver metastases surgery to cure the patient.

The reason is this. We start chemotherapy in stage 4 colorectal cancer patient with liver metastases. Initial success rates are very high, response rate of 60% to 70%. But if the metastatic stage 4 colon cancer tumor starts growing again, we need to switch chemotherapy. Colon cancer tumor response rate goes down to 10% or 20%.

In third line of metastatic stage 4 colon cancer treatment the response rate falls to 2%. Why? Are the treatments just weaker? Or what happened to the colon cancer tumor? I think what's happening is like when you have a tree. You want to cut the tree down. This is the analogy.

Sometimes we give metastatic stage 4 colon cancer patient chemotherapy. We are able to remove leaves from the tree. Then we surgically remove the metastatic stage 4 colon cancer tumors in the liver. It's like we are cutting branches of the tree. Then we remove primary colon cancer tumor. Maybe it's like cutting the stem of a tree.

But the tree always grows back. Metastatic stage 4 colon cancer tumor often returns.

Dr. Heinz-Josef Lenz, MD: How can we cure colon cancer when we are only able to cut branches from the colon cancer "tree"? We cannot unroot the tree. How do we unroot the "cancer tree"? The roots of colon cancer and other cancers are the colon cancer stem cells. Cancer stem cells are resistant to any chemotherapy treatments that we have for colon cancer patient.

How can we target cancer stem cells? We cannot kill cancer stem cells. We can only stimulate cancer stem cells so they differentiate out. Then we can kill differentiated cancer stem cells with chemotherapy. We developed and we used PRI-724 medication candidate for the first time in the clinic.

We were able to show that we can eliminate colon cancer stem cells in pre-clinical colon cancer models. Our success led to the first-in-human, proof-of-principal clinical trial. We monitored the efficacy of PRI-724 by using circulating colon cancer tumor cells.

Dr. Heinz-Josef Lenz, MD: We knew that the PRI-724 worked. We know what happens to PRI-724 molecules in the body. We monitored the cancer stem cell markers. I think for the future we need colon cancer medications that target the underlying roots of the colon cancer. These new medications will first differentiate colon cancer stem cells. Then we can kill colon cancer stem cells with chemotherapy.

I think that is how we will be able in the future to cure stage 4 colon cancer. We will cure colon cancer when we find the correct medications. They can actually differentiate cancer stem cells and kill them. We know that from other cancers that retinoic acid differentiates out leukemia cells. Then you can kill them. You can cure the cancer patient.

Probably it's not as simple in colon cancer and other cancers. But I think that is the correct approach to treat metastatic stage 4 colon cancer. PRI-724 was one of the first medications to target WNT signaling. WNT gene is altered in over 95% of colon cancer tumors.

WNT is an extremely interesting molecular pathway. Because Wnt is the first pathway that is activated in a developing life. When you have four cells, the pathway that activates first is Wnt. Because at this point you already need to know that you have to grow. But you already need to know what cells will develop into legs, into organs.

Cells of growing human body need to know their directions. It's a process of differentiation and proliferation. That has been the challenge in the past. You cannot just inhibit Wnt pathway altogether. Inhibiting both proliferation and differentiation would be too toxic.

Dr. Heinz-Josef Lenz, MD: You need to inhibit the proliferation part of Wnt pathway. But you need to stimulate the differentiation part of Wnt pathway. Then you have a chance of curing colon cancer. I think that Wnt is a key pathway in the future to develop new colon cancer treatment medications. That's the method we can use to cure stage 4 metastatic colon cancer in the future.

Colon cancer stem cells cause therapy failure. Tumor-initiating cells. Stage 4 metastatic colon cancer treatment WNT pathway inhibitor PRI-724 is effective.