When Cancer Learns to Work Around the Drug

Halda Therapeutics developed a new class of oral cancer medicines designed to selectively kill tumor cells by turning cancer’s own biology against it.

Cancer treatment has always had to contend with a difficult truth: even when a medicine works, the disease may learn to survive around it.

That is especially painful in advanced solid tumors, where patients can move through multiple lines of therapy and still watch the cancer adapt. A drug blocks one pathway, the tumor finds another. A treatment suppresses a driver, the disease mutates, amplifies, or rewires itself. What began as precision medicine can become a race against resistance.

Halda Therapeutics, a Canaan company now part of Johnson & Johnson following its $3.05 billion acquisition, was built around that problem. Founded by Yale professor Craig Crews and advanced by a team with deep experience in drug discovery and company building, Halda developed a proprietary modality called RIPTAC, or Regulated Induced Proximity Targeting Chimeras. For Canaan and our partner Tim Shannon, who was connected to Halda from its earliest company-building work and later served as chair of the board, the company sat at the center of a larger shift in oncology: the move from simply blocking cancer signals to designing medicines that can use proximity itself as a therapeutic tool.

Halda’s origins reinforce that company-building story. In 2019, following the success of Arvinas, another Canaan portfolio company that Crews and Shannon had helped start, they helped launch Halda. The company quickly attracted talent and investors around the idea that induced proximity could support an entirely new class of medicines. From the outset, the opportunity combined differentiated academic science with experienced company building and a modality that could extend beyond a single program.

For decades, much of targeted cancer therapy has followed a relatively intuitive idea: find a molecular driver of the disease, then inhibit it. If a protein is helping a tumor grow, the drug should bind to that protein and shut it down. In many cancers, that approach changed the standard of care and gave patients more precise options than older chemotherapy alone.

The limitation is that cancer is not static. Tumors are living systems under pressure. When a drug blocks one route, the disease can develop mutations, amplify the target, activate bypass pathways, or change which signals it depends on. In prostate cancer, for example, therapies that interfere with androgen receptor signaling can be effective for a time, but metastatic castration-resistant disease often finds ways to keep growing despite those interventions.

That is why resistance has become one of the defining challenges in oncology. The problem is not that precision medicine failed. It is that precision needs to keep evolving as the disease evolves.

The simplest version of a cancer drug is one that attacks tumor cells and leaves healthy tissue alone. The hard part is that cancer cells are made from the body’s own machinery. They often use the same proteins, pathways, and survival systems normal cells need. A medicine must be powerful enough to matter, selective enough to avoid unacceptable toxicity, and durable enough to stay useful as the tumor changes.

That balance is particularly difficult in solid tumors. Many cancers do not present a single clean target. Even when a target is present, it may not be enough to block it directly. The disease may continue to express a protein after it no longer depends on that protein in the same way, or it may carry molecular features that make conventional inhibition less effective.

Halda’s work started from a different question: what if the target did not need to be inhibited in the old sense? What if its presence on the cancer cell could be used as an address?

In plain English, Halda’s RIPTAC medicines are designed to bring two proteins together inside a cancer cell: one protein that helps identify the tumor cell, and another protein that performs an essential cellular function. By holding those proteins together in a defined way, the medicine is intended to interfere with that essential function selectively in the cancer cell, leading to tumor cell death while sparing cells where the cancer-associated targeting protein is absent or minimally expressed.

Halda describes this as a “hold and kill” mechanism. The phrase is useful because it gets at the heart of the idea. The drug is not merely occupying a target. It is creating a new molecular interaction with a specific purpose.

The company’s lead program, HLD-0915, is an oral RIPTAC therapy in development for metastatic castration-resistant prostate cancer. It is designed to use the androgen receptor, which remains highly relevant in many prostate tumors, as the tumor-selective targeting protein, and BRD4, a protein involved in transcriptional regulation, as the essential-function protein. Halda has also built programs in breast cancer and other solid tumors, pointing to the broader ambition behind the platform.

Halda arrived at a moment when induced-proximity science was becoming more than an elegant biological idea. The broader field had already shown that small molecules could be designed to bring proteins together and create new cellular outcomes, as seen in protein degraders and molecular glues. At the same time, oncology was running into the practical limits of therapies that depend mainly on direct inhibition.

That combination mattered. Scientists had better tools for designing heterobifunctional molecules, better understanding of tumor biology, and clearer evidence that resistance was not a side problem but a central problem. The question was whether a company could turn those pieces into a drug modality with a coherent clinical path.

Halda’s answer was to begin with common solid tumors where resistance creates urgent unmet need and where the biology could support selectivity. The early focus on prostate and breast cancer was not incidental. These are large diseases with substantial treatment histories, known molecular features, and patients who need better options after existing therapies stop working.

Halda’s distinctiveness is not simply that it works in oncology, or even that it works in induced proximity. The important idea is that the company designed a modality around cancer-selective killing without requiring the cancer target to remain a classic vulnerability.

That is a subtle but meaningful shift. In many therapies, the target must be both present and functionally necessary. Halda’s RIPTAC approach is designed to use a tumor-associated protein as a locator and then create a new interaction that disables an essential function in that tumor cell. If that logic translates clinically, it could open a wider design space for cancers that continue to express useful markers but no longer respond to conventional blockade.

The oral small-molecule format also matters. Cancer care does not happen only in academic centers or specialized infusion clinics. An oral medicine, if proven safe and effective, can fit more naturally into the way many patients already receive care, including in community oncology settings.

At Canaan, we are drawn to companies that make a difficult future feel newly possible. Halda stood out because it was not asking whether another inhibitor could be built against a familiar pathway. It was asking whether proximity could be engineered into a new way of killing cancer cells selectively.

The company also reflected a pattern Canaan values in biotech company formation: deep academic science, a clear therapeutic problem, and the discipline to turn a platform into specific medicines. Crews’ scientific work gave Halda a serious foundation. The company’s progress from platform concept to clinical-stage program, and ultimately to Johnson & Johnson’s acquisition, showed that the idea could move beyond the lab into a development path large pharma believed was worth advancing.

Canaan’s involvement followed the company-building model we use in biopharma: identify promising early science, help shape strategy from the outset, assemble the founding team, and partner with a knowledgeable investor syndicate. In 2024, as Halda transitioned into a clinical-stage company, Canaan executive in residence Chris Schade became president and CEO. That sequence is what the early thesis looked like in practice: build around differentiated science, turn the platform into specific medicines, and add operating leadership as the company moved toward patients.

For most people, the technical distinction between an inhibitor, a degrader, and a RIPTAC may not matter. What matters is the possibility that cancer drugs can become more adaptive to the ways cancer actually survives.

Patients with advanced disease often live with a brutal sequence: hope, response, resistance, and the search for another option. Families experience cancer not as a pathway diagram but as time gained or lost, symptoms controlled or not, choices remaining or exhausted. Medicines that can work after resistance emerges are not just scientific achievements. They can change the emotional and practical reality of treatment.

The question Halda is asking is not simply whether one oral therapy can help treat advanced prostate cancer. It is whether drug designers can turn cancer’s remaining identifiers into points of attack, even after the disease has learned to escape older approaches.

If Halda’s work succeeds inside Johnson & Johnson, it points toward a future where precision oncology becomes less brittle. Not a world where cancer stops evolving, but one where medicines are designed with that evolution in mind from the beginning. That is the constraint Halda set out to loosen: the idea that once a tumor works around the drug, the drug’s logic has run out. Halda’s deeper contribution is the belief that biology can be reassembled into new therapeutic possibilities, and that resistance, while real, does not have to be the end of the story.