Rewiring BCL6 To Trigger Cell Death
A conversation between Steve Worland, CEO, Shenandoah Therapeutics, and Morgan Kohler
Cancer is driven by proteins that promote tumor growth and survival. Most targeted therapies are designed to inhibit or degrade these proteins. But cancer can adapt, activate alternative pathways, and ultimately develop resistance.
Shenandoah is rewiring oncogenic drivers, specifically BCL6, to bypass resistance and directly trigger the cell’s natural self-destruct machinery. We connected with Steve Worland, CEO of Shenandoah Therapeutics, to learn more about this approach.
Shenandoah's approach uses chemically induced proximity to redirect oncogenic proteins toward activating programmed cell death, rather than simply inhibiting or degrading them. What are the key molecular events that enable this change in protein function, and what makes this strategy feasible from a drug discovery perspective?
Our approach represents a fundamental shift in how we think about targeting cancer-driving proteins. Rather than simply blocking or eliminating an oncogenic protein, we use chemically induced proximity to redirect its activity toward triggering cancer cell death.
Our Transcriptional and Epigenetic Chemical Inducers of Proximity (TCIP) molecules bring together proteins that do not ordinarily interact in this way, recruiting transcriptional or epigenetic regulatory machinery to oncogenic proteins bound to specific regions of DNA. This changes the transcriptional output from repression of cell-death pathways to activation of those same pathways, ultimately inducing apoptosis.
What makes this particularly exciting from a drug discovery perspective is that we can leverage small molecule chemistry and existing protein-binding interactions to create entirely new biological functions. We are not limited to conventional inhibition or degradation. Instead, we can potentially turn proteins that cancers depend on into liabilities that actively drive their destruction.
BCL6 normally represses genes involved in programmed cell death and plays a role in B-cell malignancies. What features of BCL6 make it a compelling target for this approach, and what evidence supports its ability to be redirected from a cancer-promoting role to a cancer-killing one?
BCL6 is an especially compelling target because it plays a central role in maintaining the survival of certain B-cell malignancies by repressing genes involved in apoptosis.
Importantly, BCL6 is already positioned at the genomic sites controlling these cell-death pathways. Rather than eliminating the protein, our strategy takes advantage of its natural DNA-binding activity and localization to specific chromatin sites to recruit transcriptional machinery capable of activating the very genes it would normally suppress.
Foundational research published in Nature, Science, and Cell has demonstrated that chemically induced proximity can redirect BCL6-associated transcriptional activity and trigger apoptosis in lymphoma cells. Shenandoah's lead molecules have also demonstrated potent preclinical activity, including complete and durable tumor regression in in vivo B-cell lymphoma models.
These findings support the potential to transform BCL6 from a driver of cancer cell survival into a mechanism for inducing cancer cell death.
How do your lead therapeutic candidates alter BCL6's interactions with its binding partners or regulatory machinery to activate pro-apoptotic gene expression? Which molecular and cellular assays have been most important in establishing this mechanism?
Our TCIP approach is designed to create new interactions between BCL6 and transcriptional regulatory machinery, effectively changing the function of BCL6 at specific genomic locations.
Foundational studies have shown that recruiting transcriptional activators, including BRD4, CDK9-associated machinery, or the acetyltransferases p300/CBP, to BCL6-bound regions can activate previously suppressed pro-apoptotic genes. This represents a gain-of-function mechanism rather than traditional inhibition.
Establishing this mechanism requires connecting several levels of evidence: formation of the induced protein complex, changes in transcriptional activity, activation of apoptosis-related genes, and ultimately selective cancer cell killing.
Techniques such as biochemical binding and complex-formation assays, transcriptional profiling, chromatin analysis, and cellular apoptosis assays are particularly valuable in establishing these relationships.
Our focus is on demonstrating that these molecular events translate into meaningful and durable antitumor activity.
During the discovery and optimization of your therapeutic candidates, which chemical or structural properties have proven most important for achieving the desired proximity-dependent activity? How do you balance target engagement, potency, selectivity, and drug-like properties?
One of the most important lessons from chemically induced proximity is that simply binding two proteins is not enough. The geometry, orientation, and stability of the resulting complex can be critical determinants of biological activity.
We therefore consider the entire induced protein complex, not just the binding affinity of each component. Linker architecture, molecular flexibility, and favorable protein-protein interactions can all influence whether a molecule produces the desired transcriptional response.
Our objective is to optimize potency and selectivity alongside the properties required of a viable therapeutic, including solubility, permeability, pharmacokinetics, and tolerability.
The broader opportunity is to use medicinal chemistry to engineer new biological functions rather than merely optimize inhibition of an existing target. This expands the possibilities for creating differentiated small molecule cancer medicines.
Your press release describes complete and durable tumor regression in preclinical B-cell lymphoma models. What experimental findings distinguish these responses from temporary tumor growth inhibition, and what evidence suggests that the observed regressions are directly attributable to the intended mechanism of action?
The distinction between inhibiting tumor growth and eliminating tumor cells is central to our therapeutic strategy.
Traditional targeted therapies often suppress the pathways cancers depend on, but the underlying malignant cells may survive and eventually resume growing. Our approach is designed to actively induce apoptosis, creating the potential for deeper and more durable responses.
In preclinical studies, Shenandoah's lead molecules have demonstrated complete and durable tumor regression, including in patient-derived B-cell lymphoma models harboring multiple cancer-driving mutations.
The mechanistic foundation for these findings comes from studies demonstrating that induced proximity can activate BCL6-repressed pro-apoptotic pathways and trigger cancer cell death. Importantly, the activity of our TCIPs is dependent on BCL6 expression, confirming the mechanistic link to the target. Taken together, these results provide encouraging evidence that transcriptional reprogramming may offer advantages beyond conventional inhibition or degradation.
Our next priority is to establish the durability, reproducibility, and translational relevance of these responses as we advance toward clinical development.
How might cancer cells develop resistance to a therapy that redirects an oncogenic protein to activate apoptosis, and what experiments are you conducting to identify potential resistance mechanisms before clinical development?
Resistance is an important consideration for any targeted cancer therapy. Shenandoah TCIPs were designed with resistance in mind — in fact, designed to be resistant to resistance. This doesn’t mean resistance will never occur, but we expect a high barrier to resistance. This is inherent in the multiplicity of cell-death pathways activated and in the gain-of-function mechanism itself. Because multiple cell-death pathways get activated, resistance arising through inactivation of one cell-death pathway will still leave the tumor cell experiencing activation of other cell-death pathways. And because it’s gain of function, even if one copy of the BCL6 or BRD4 gene develops a resistance mutation, the other copy will remain sensitive and lead to activation of cell-death pathways.
Potential resistance mechanisms could include changes in target expression, alterations in the proteins involved in forming the induced complex, or adaptations in the downstream apoptotic machinery, but more than one mutation is likely to be required.
As we advance development, understanding the relationship between target expression, transcriptional response, and sensitivity to treatment will be important for identifying responsive patient populations and informing potential combination strategies.
Because BCL6 also has normal biological functions in B-cell development, how are you evaluating the therapeutic window of your approach?
Establishing an appropriate therapeutic window is a critical priority, particularly because BCL6 has important physiological functions in normal B-cell development and germinal center biology.
Our approach is designed to exploit the transcriptional dependencies of malignant cells, where BCL6 plays an important role in suppressing apoptosis. The objective is to achieve potent antitumor activity while limiting unwanted effects on normal tissues, which is what we have seen in the first in vivo disease models.
This requires careful evaluation of tumor selectivity, exposure-response relationships, and the consequences of modulating BCL6-associated transcriptional pathways in healthy cells.
As we approach IND-enabling studies, these assessments will be central to selecting appropriate dosing strategies and establishing a safety profile that supports clinical development.
As the lead BCL6 program approaches IND-enabling studies, which pharmacokinetic, pharmacodynamic, and toxicology findings will be most critical to establishing that the mechanism can translate into a clinically viable therapy? Are there specific biomarkers that could demonstrate target engagement and pathway activation in future clinical studies?
Our priority is to establish a clear relationship between drug exposure, target engagement, activation of the intended transcriptional program, and antitumor activity.
From a pharmacokinetic perspective, we want to achieve sufficient exposure to drive the desired biological response. Because we trigger a response based on encounters between proteins rather than maintaining inhibition of a protein, we don’t expect to need continuous target engagement for activity. Pharmacodynamically, it will be important to demonstrate that this exposure translates into activation of BCL6-repressed apoptotic pathways.
Potential biomarkers include changes in the expression of pro-apoptotic target genes, downstream markers of apoptosis, and tumor response. These could provide important evidence that the intended mechanism is functioning in patients.
Equally important will be establishing an acceptable safety profile and understanding how the mechanism affects normal tissues.
Ultimately, successful translation will depend on demonstrating that the compelling activity observed in preclinical models can be achieved at exposures that are clinically tolerable.
Shenandoah is also exploring other oncogenic drivers and solid tumors. What biological criteria determine whether a protein is suitable for chemically induced proximity-based reprogramming, and how do you assess whether this mechanism can be extended to targets that have been difficult to address with conventional inhibitors or degraders?
We believe chemically induced proximity has the potential to expand the universe of therapeutically actionable cancer targets.
An attractive target typically has a well-defined role in cancer biology, a relationship with transcriptional or cellular survival pathways, and the potential to be redirected through induced interactions with other proteins. As exemplified by natural products, such as rapamycin, the range of proteins that can be induced to connect through chemically induced proximity is quite broad and doesn’t require a prior biological link between the proteins.
BCL6 provides an important proof of concept because its natural role in repressing pro-apoptotic genes creates an opportunity to reverse that function and actively trigger cancer cell death.
However, we do not believe this approach is limited to BCL6 or B-cell malignancies. Our broader strategy is to identify oncogenic drivers whose biological activities can be reprogrammed to create therapeutic effects that conventional inhibitors or degraders cannot achieve.
As we expand into additional cancer drivers and solid tumors, our focus is on applying this principle systematically to develop a broader pipeline of differentiated small molecule cancer therapeutics.
About The Expert
Steve Worland, Ph.D., brings more than 30 years of biotechnology leadership, drug discovery, and development experience as CEO of Shenandoah. Most recently, he served as chief executive officer of Numerion Labs. He previously cofounded eFFECTOR Therapeutics and served as its president, chief executive officer, and board member, leading the oncology company from inception through its public listing in 2021 and advancing two product candidates from target concept into Phase 2 clinical development. Prior to eFFECTOR, Worland served as president and chief executive officer of Anadys Pharmaceuticals, where he led the company through its $230 million acquisition by Roche.