Reprogramming Aggressive Prostate Cancer to Enable Immune mediated Tumor Elimination

Reprogramming Aggressive Prostate Cancer to Enable Immune mediated Tumor Elimination - Paul Mathew - YouTube

Breaking the Cold Tumor Barrier: New Bispecific Antibody Targets Hidden Enemy in Prostate Cancer

BLUF (Bottom Line Up Front): Researchers at Tufts Medical Center have developed a novel bispecific antibody that could transform prostate cancer treatment by targeting aggressive "basal-type" cancer cells that evade the immune system, resist hormone therapy, and drive bone metastases. By simultaneously blocking two integrin proteins (alpha-5 and alpha-V), the antibody disrupts the mechanical signaling that allows cancer cells to hide from immune surveillance, potentially making prostate cancer responsive to immunotherapy for the first time. The treatment is being prepared for first-in-human clinical trials within the next year through spinout company Jolian Therapeutics.

The Hidden Architecture of Aggressive Prostate Cancer

For over two decades, Dr. Paul Mathew at Tufts Medical Center has been obsessed with a medical puzzle: Why does prostate cancer behave in such a predictable pattern, spreading to bone in 90% of metastatic cases? His research has uncovered what he calls a "Rosetta stone" for understanding lethal prostate cancer—and potentially treating it in revolutionary ways.

The answer lies not in genetic mutations alone, but in the physical forces and cellular architecture that govern cancer behavior. Mathew's team has discovered that prostate cancers contain a mixture of two distinct cell types that mirror the normal prostate gland: luminal cells (which respond to hormones and express PSA) and basal cells (which anchor to their environment and resist standard treatments).

"Tumors have a very powerful memory of the gland from which they arose," Mathew explained in a recent presentation to the Informed Prostate Cancer Support Group. "It's not that cancers are either basal or luminal—they contain admixtures of the two in varying proportions. The tumors that are more basal than luminal are the more aggressive ones."

The Basal-Luminal Paradigm: A New Way to Understand Prostate Cancer

Research analyzing over 600 men with metastatic castration-resistant prostate cancer (mCRPC) at UCSF and other institutions revealed that approximately 55% had basal-enriched tumors while 45% had luminal-enriched tumors. This distinction matters profoundly for treatment.

Luminal cells are regulated by androgens (male hormones) and express the androgen receptor—which is why hormone therapy works, at least initially. They also express PSMA, making them visible to PSMA-targeted scans and vulnerable to treatments like Pluvicto (lutetium-177-PSMA-617).

Basal cells, however, lack androgen receptors and express low levels of PSMA. Instead, they're controlled by a completely different mechanism involving physical forces, integrins (proteins that connect cells to their environment), and a transcription factor called MYC that drives over 70% of human cancers.

"Most therapies target the luminal phenotype," Mathew noted. "If you target only basal cells, the luminal cells will drift towards the basal phenotype. If you target only luminal cells, basal will dominate. The future is combining basal and luminal targeting."

Force Matters: The Mechanical Biology of Cancer

Mathew's breakthrough insight involves understanding how physical forces shape cancer behavior—a concept called mechanotransduction. When cancer cells attach to stiff environments like bone through integrin proteins, they trigger a cascade of events:

1. Integrins connect the cell to the surrounding matrix (fibronectin and other proteins)
2. This creates mechanical tension within the cell's internal skeleton
3. The tension activates a protein called YAP, which moves into the nucleus
4. YAP "bookmarks" and enables MYC, amplifying its cancer-promoting programs
5. MYC shuts down immune recognition, creating a "cold tumor" invisible to immune cells

"Force matters in biology," Mathew emphasized, noting recent research suggesting dietary microplastics might contribute to early-onset colorectal cancers by stiffening tissue. "Stiffness means one fate, softness means another fate."

The bone marrow provides an ideal stiff environment for prostate cancer cells. The cancer cells secrete signals that activate bone-forming cells (osteoblasts), which reciprocally support tumor growth—explaining the characteristic bone-forming (osteoblastic) rather than bone-destroying (osteolytic) pattern of prostate cancer metastases.

The Bispecific Antibody Solution

Mathew's team developed a bispecific antibody that simultaneously targets both alpha-5 and alpha-V integrins. Unlike bispecific T-cell engagers (which connect T-cells to cancer cells), this antibody works by:

1. Disrupting mechanical signaling: Binding both integrins prevents them from transducing force signals
2. Forcing integrin degradation: The antibody causes cells to internalize and destroy the integrins
3. Collapsing the force architecture: Without functional integrins, YAP can't activate MYC
4. Restoring immune visibility: The tumor begins secreting chemokines that attract immune cells
5. Enabling immune destruction: Natural killer cells and macrophages infiltrate and eliminate tumor cells

Preclinical studies published by Mathew's team demonstrated that the antibody:

• Downregulated the entire basal gene signature in prostate cancer cells
• Upregulated immune response genes
• Eliminated aggressive androgen-receptor-negative tumors in mouse models
• Required natural killer cells to work (depleting NK cells eliminated the antibody's efficacy)
• Controlled tumors from men who donated tissues to rapid autopsy programs

"We're targeting three major pillars of immunosuppression: MYC, TGF-beta, and EMT (epithelial-mesenchymal transition)," Mathew said. "These integrin proteins are key to all three across a wide variety of cancers."

Why Prostate Cancer Resists Immunotherapy—Until Now

Checkpoint inhibitors like pembrolizumab (Keytruda) and nivolumab (Opdivo) have revolutionized treatment for melanoma, lung cancer, and many other malignancies but have largely failed in prostate cancer. Mathew's research explains why: the basal phenotype driven by integrin-YAP-MYC signaling creates profoundly immunosuppressive "cold tumors" that immune cells can't recognize or infiltrate.

"If we are essentially tackling the major obstacle to immunotherapy in prostate cancers—which I would propose we are—then we may make a transformational advance in allowing immune checkpoint inhibitors to play a genuine and substantive role," Mathew said.

The research also explains why hormone therapy eventually fails: intensive androgen deprivation drives the tumor composition toward the basal phenotype, creating treatment-resistant disease. This plasticity—the ability of tumors to shift between luminal and basal states—underlies progression to castration resistance.

Clinical Development Timeline and Vision

Mathew and colleague Dr. Ragav Joshi have formed Jolian Therapeutics (a Delaware C-corp) to advance the antibody toward clinical trials. The team needs to:

• Secure funding from venture capital or pharmaceutical partners
• Complete IND-enabling studies demonstrating safety
• Submit an Investigational New Drug application to the FDA
• Launch first-in-human Phase 1 trials

"Hopefully not more than a year to get this into the first-in-human trial," Mathew projected. "We certainly think the science is very robust. The antibody's very robust. We just need the dollars and the team around us."

The antibody has favorable characteristics for clinical development:

• Can be manufactured at scale
• Shows appropriate drug-like properties
• Targets both tumor cells and the bone microenvironment
• Works through immune activation rather than direct cell killing

Potential Treatment Paradigms

Mathew envisions several potential applications:

High-Risk Localized Disease: Could the antibody combined with short-course hormone therapy eliminate high-risk prostate cancer without surgery or radiation? "That is a bit of an imaginative leap, I must concede, but it is along the lines of what we must think of as a research community to make transformative advances," Mathew acknowledged. He noted that in bladder cancer, combinations of antibody-drug conjugates and immunotherapy achieve complete responses in over 50% of aggressive organ-confined tumors, allowing bladder-sparing treatment.

Metastatic Disease: A triple combination of the bispecific antibody, hormone therapy, and immune checkpoint inhibitors could target both basal and luminal compartments while stimulating immune responses. "That triple combination might serve to eliminate—it's dual basal and luminal targeting that is immunogenic," Mathew suggested.

Minimal Toxicity Approach: By working through immune activation rather than direct cytotoxicity, the treatment might avoid the severe side effects of chemotherapy while minimizing the burden of extended hormone therapy.

Companion Diagnostics and Patient Selection

Mathew's team has studied integrin expression patterns across prostate cancer stages:

• Absent in normal luminal prostate tissue
• Increasingly expressed in higher-grade primary tumors
• Present in 70% of bone metastases (tumor cells)
• Present in 95% of tumor-associated bone vasculature
• Present in metastases to other organs

"If you see clinical evidence of metastatic prostate cancer to bone, almost certainly we think these integrins are implicated," Mathew said.

For more precise patient selection, the team is developing an integrin-MYC transcriptional signature as a companion diagnostic in collaboration with Caris Life Sciences. This genomic signature would complement existing DNA mutation testing to identify patients most likely to benefit.

Current commercial genetic testing panels (Foundation Medicine, Caris, Guardant) focus on targetable mutations but don't assess the integrin-MYC pathway that Mathew believes represents "the foundational biology of the disease."

Implications for PSMA-Targeted Treatments

The research has important implications for understanding PSMA-based therapies like Pluvicto and bispecific antibodies. PSMA is primarily a luminal marker—patients with very low PSA and aggressive basal-enriched disease often show weak or negative PSMA PET scans and require FDG-PET imaging instead.

"You can get progression with Pluvicto and all the bispecifics targeting PSMA because many of them are focusing on luminal markers, almost none are focusing on basal-defined markers," Mathew explained. "You're hammering away at that PSA, which is fine because that is a bulk of the tumor and you can prolong life, but you're not going to cross a transformative boundary defined by that basal phenotype that resists immune surveillance."

This doesn't diminish the value of PSMA-targeted treatments—they effectively target the luminal compartment. But optimal outcomes may require combining luminal-targeted and basal-targeted approaches.

The Neuroendocrine Connection

The basal phenotype also gives rise to neuroendocrine prostate cancer (NEPC), an extremely aggressive variant that:

• Arises from basal-type cells
• Spreads to liver and causes bone destruction rather than bone formation
• Can metastasize to brain
• Shows low PSA and weak PSMA expression
• Involves switching from c-MYC to N-MYC

"At the heart of that is a MYC variant, N-MYC as opposed to c-MYC," Mathew explained, suggesting the integrin-targeting approach might also address this treatment-refractory complication.

Rethinking Personalized Medicine

Mathew argues for expanding the definition of personalized medicine beyond genomic sequencing:

"Sequencing the genome isn't telling us how the cancer is behaving. It doesn't explain how the cancer is behaving. But by thinking about them in basal and luminal trajectories and understanding what defines basal and the central role of integrins in that—that defines the biology. All these mutations whether it's p53 or PTEN or BRCA, they converge on these integrins in diverse ways to explain the disease phenotype."

He advocates for a new paradigm combining:

• Genomic analysis (mutations in DNA repair genes, p53, PTEN, etc.)
• Transcriptomic analysis (basal vs. luminal gene signatures)
• Integrin-MYC pathway assessment
• Dual targeting strategies for both tumor compartments

Broader Cancer Applications

While focused on prostate cancer, Mathew believes the integrin-targeting approach has wider applicability. Alpha-5 and alpha-V integrins play key roles in:

• Pancreatic cancer and other fibrotic tumors
• TGF-beta activation in tumor stroma
• Embryonic development and stem cell programs
• Metastatic colonization across cancer types

"We think these two integrins have a lot to do with it across a wide variety of cancers, largely because they are recapitulation of embryonic phenotype integrins," Mathew noted. "These integrins are key to embryogenesis."

Why Past Integrin Therapies Failed

There's considerable skepticism about integrin-targeted therapies because previous attempts largely failed. Mathew explains this through his research findings:

"People have been studying them for a long time, but why hasn't there been advances in the clinic? Because of the interaction between integrin alpha-5 and alpha-V and the absolute necessity to target both of them with a very effective modality such as a bispecific antibody. If you studied only one integrin, the other one is robustly compensating."

Even more problematic: "You could accelerate the disease by targeting one because the other one rears up and compensates. We can see bone formation increasing if we block the alpha-V integrin without blocking the alpha-5."

Using two separate monoclonal antibodies doesn't work well either—the bispecific format is essential to force simultaneous integrin degradation.

Honoring Scientific Foundations

Mathew paid tribute to Dr. Richard Hynes, the MIT professor who discovered integrins and fibronectin and passed away recently. "Obviously a legend, and on whose broad shoulders we all stand," Mathew said, acknowledging that current integrin research builds on decades of foundational work.

What Patients Should Know

For patients and caregivers, several key points emerge:

1. This research explains treatment patterns: Why hormone therapy works initially but eventually fails, why bone metastases form, why immunotherapy hasn't worked in prostate cancer, and why some patients progress rapidly despite treatment.

2. Clinical trials are coming: While not yet available, first-in-human trials are expected within a year. The treatment would likely be studied first in metastatic castration-resistant disease.

3. Combination approaches are key: Future treatment strategies should target both luminal (hormone-sensitive, PSMA-positive) and basal (hormone-resistant, immunosuppressive) tumor compartments.

4. Current treatments remain important: PSMA-targeted therapies, hormone treatments, and other standard approaches effectively target the luminal compartment and provide meaningful clinical benefit.

5. Genomic testing has limitations: Current commercial tumor sequencing panels, while valuable for identifying BRCA mutations and other targetable alterations, don't assess the integrin-MYC pathway that may drive aggressive disease.

6. Immune-based approaches may become viable: If successful, the integrin-targeting antibody could make prostate cancer responsive to checkpoint inhibitors and other immunotherapies that have transformed outcomes in other cancers.

Questions for Your Oncologist

Patients interested in this research might ask:

• Does my tumor have basal-enriched or luminal-enriched characteristics?
• How is my tumor assessed beyond genetic mutations?
• Would I be a candidate for clinical trials of integrin-targeting or immune-based therapies?
• How does my PSMA PET scan appearance relate to my tumor biology?
• Are there trials combining different targeting approaches?

The Path Forward

Mathew's research represents a fundamental reconceptualization of prostate cancer biology, moving beyond genetic mutations to understand how physical forces and cellular architecture drive aggressive disease. By targeting the mechanical signaling that allows cancer cells to evade immune surveillance, the approach addresses what may be "the major obstacle to immunotherapy in prostate cancers."

Success would represent more than an incremental advance—it could fundamentally change the treatment paradigm from managing metastatic disease to potentially curing it by enabling the immune system to recognize and eliminate cancer cells.

As Mathew concluded: "We need a new paradigm of thinking of combining basal and luminal targeting for the reasons I've explained, and a new way of thinking about personalized medicine beyond genomics sequencing alone."

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Verified Sources and Citations

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2. Aggarwal, R., et al. (2018). "Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study." Journal of Clinical Oncology, 36(24), 2492-2503. https://ascopubs.org/doi/10.1200/JCO.2017.77.6880

3. Abida, W., et al. (2019). "Genomic correlates of clinical outcome in advanced prostate cancer." Proceedings of the National Academy of Sciences, 116(23), 11428-11436. https://www.pnas.org/doi/10.1073/pnas.1902651116

4. Hamid, A.A., et al. (2019). "Compound Genomic Alterations of TP53, PTEN, and RB1 Tumor Suppressors in Localized and Metastatic Prostate Cancer." European Urology, 76(1), 89-97. https://www.europeanurology.com/article/S0302-2838(18)30917-5/fulltext

5. Bluemn, E.G., et al. (2017). "Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling." Cancer Cell, 32(4), 474-489. https://www.cell.com/cancer-cell/fulltext/S1535-6108(17)30361-X

6. Dupont, S., et al. (2011). "Role of YAP/TAZ in mechanotransduction." Nature, 474(7350), 179-183. https://www.nature.com/articles/nature10137

7. Hynes, R.O. (2002). "Integrins: Bidirectional, Allosteric Signaling Machines." Cell, 110(6), 673-687. https://www.cell.com/cell/fulltext/S0092-8674(02)00971-6

8. Dang, C.V. (2012). "MYC on the Path to Cancer." Cell, 149(1), 22-35. https://www.cell.com/cell/fulltext/S0092-8674(12)00353-5

9. National Cancer Institute. (2024). "Prostate Cancer Treatment (PDQ®)–Health Professional Version." https://www.cancer.gov/types/prostate/hp/prostate-treatment-pdq

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11. Sartor, O., et al. (2021). "Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer." New England Journal of Medicine, 385(12), 1091-1103. https://www.nejm.org/doi/full/10.1056/NEJMoa2107322

12. Graff, J.N., et al. (2016). "Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer." Oncotarget, 7(33), 52810-52817. https://www.oncotarget.com/article/10547/text/

13. Pritchard, C.C., et al. (2016). "Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer." New England Journal of Medicine, 375(5), 443-453. https://www.nejm.org/doi/full/10.1056/NEJMoa1603144

14. Jolian Therapeutics. (2024). Company website and regulatory filings. Delaware Secretary of State business entity records.

15. Tufts Medical Center. (2024). "Cancer Research." https://www.tuftsmedicalcenter.org/research-clinical-trials/research-areas/cancer-research

Note: This article is based on Dr. Mathew's January 2025 presentation and publicly available research. The bispecific antibody discussed is investigational and not yet approved by regulatory authorities. Patients should discuss all treatment decisions with their oncologists and not make changes based on preliminary research findings.

Disclaimer: This information is provided for educational purposes and does not constitute medical advice. Always consult with qualified healthcare professionals regarding your specific medical situation.