Overcoming drug resistance with General Oncology

DDW Editor Reece Armstrong speaks to Jeff Glazier, CEO of General Oncology, about the challenges facing pancreatic cancer drug development and the company’s activities in the space.

RA: Why has pancreatic cancer remained so difficult to treat?

JG: Pancreatic cancer is typically diagnosed at an advanced stage, is biologically aggressive, and rapidly develops resistance to therapy. Tumours are highly heterogeneous, both between patients and within the same tumour, and are supported by a dense stromal environment that can limit drug penetration. 

RA: What have been the biggest drug development challenges facing pancreatic cancer?

JG: As with other cancers, tumour cell evolution and the consequent drug resistance have remained the biggest challenge. Every cancer cell is genetically distinct. Given a sufficiently large total disease burden, the probability that resistance emerges to any single drug is statistically almost certain. 

For that reason, no single drug is likely to provide a high cure or control rate in metastatic cancers, including pancreatic cancer. Combination therapy faces the same challenge if the drugs share overlapping mechanisms of action. Adding more drugs can also increase toxicity, which constrains dosing.  

The ultimate objective should be rationally designed combinations whose components act through independent mechanisms and whose cumulative toxicity profile remains low. 

RA: Are you encouraged by new therapies increasing the cancer-survival rate?

JG: There has certainly been meaningful work across the field, and it has made a real difference for patients and their families. 

And yet a high cure or control rate has remained elusive for most solid metastatic cancers. That suggests the central biological challenge has not been adequately addressed. 

Cancer is an evolving system. When one applies selective pressure with a targeted therapy, it is common to see an initial response followed by resistance as surviving cells adapt. I believe the next phase of progress will come from designing therapies with tumour evolution in mind—approaches that make resistance substantially more difficult to develop, rather than simply delaying it. 

RA: You’ve presented early data showing positive progression-free survival for two patients. Whilst only a small sample, how encouraging is this data for moving forward into future trials?

JG: In the SHARON trial, two stage IV pancreatic cancer patients remain progression-free 48 and 28 months after receiving just two cycles of therapy, with no further cancer treatment.  

In a subset of five patients who had fewer prior lines of therapy and had stable or responding disease at enrolment, median progression-free survival was approximately 14.2 months. This is approximately double the median progression-free survival reported in the POLO trial, which is the closest contemporary benchmark. Notably, there have been no reported long-term side effects in the SHARON trial. 

In the SHARON trial, patients receive two cycles of the investigational treatment approximately six weeks apart, followed by surveillance with periodic CT scans and exams, without additional cancer treatment. 

As with any Phase I trial, the population is heterogeneous, and in the SHARON trial many participants had received and progressed on multiple prior therapies, substantially increasing the likelihood of drug resistance. Efficacy must ultimately be confirmed in a well-designed Phase II study where treatment is administered earlier in the disease course. 

RA: Could you talk about the approach behind the SHARON trial and how it’s designed to overcome drug resistance?

JG: The SHARON trial uses a prototype for GO-4305C, which refers to our novel prodrug GO-4305 as co-packaged with melphalan, carmustine, and ascorbic acid. In the prototype, hydroxocobalamin is used in place of GO-4305. 

By design, this combination is highly synergistic and attacks cancer cells in multiple independent ways while seeking to avoid long-term toxicity. An in vitro study using BRCA-wildtype MIA PaCa-2 pancreatic cancer cells demonstrated greater than a 6.8-log reduction in clonogenic survival, killing approximately 6,300 times as many cancer cells as melphalan alone (6.8-log vs. 3-log reduction). 

GO-4305C is designed to disrupt intracellular redox balance in a manner that impairs all major DNA repair pathways, including homologous recombination, non-homologous end joining and alternative end joining, single-strand annealing, base excision repair, nucleotide excision repair, translesion synthesis, and MGMT-mediated repair. In addition, it is designed to kill cancer cells through multiple independent mechanisms, including DNA damage, ATP depletion, inhibition of glycolysis, and overactivation of PARP. It is also designed not to depend on any specific cell membrane transporter, reducing vulnerability to transporter-mediated resistance. 

RA: How did the diagnosis of your aunt inspire the creation of General Oncology?

JG: In 2012, Sharon was diagnosed with pancreatic cancer in the setting of an inherited BRCA mutation. After Whipple surgery, she received two cycles of melphalan to address micrometastatic disease—metastases too small to be detected by imaging. Melphalan was chosen because it is not typically associated with chronic toxicities and because of its log-linear dose-response curve. With the drug, it was theoretically possible to get curative log reductions in a BRCA-related cancer with a micrometastatic tumour burden. 

Nearly 14 years later, she remains pancreatic cancer-free and has experienced no lasting side effects. We are deeply grateful to Dr Andreas Klein at Tufts Medical Center for treating her with that off-label approach. 

We subsequently built on that experience to develop GO-4305C, with the goal of addressing drug resistance in patients with higher tumour burdens. The SHARON trial is named in her honour. 

RA: You’re also exploring other areas of oncology including ovarian, prostate and breast cancers. What’s the potential of GO-4305C in treating these cancers?

JG: GO-4305C is designed for solid metastatic cancers more broadly. BRCA-related ovarian, prostate, and breast cancers are of interest, as well as non-BRCA variants of those cancers and other solid tumours, including colon cancer. 

RA: What are the company’s plans moving into 2026?
 

The Phase I expansion of the SHARON trial is open for enrollment and is expected to enroll approximately 12 additional patients. The expansion includes both BRCA and non-BRCA pancreatic cancer, as well as BRCA-associated breast cancer. 

We also have additional pipeline candidates. One is GO-2301, designed for both oncology and ophthalmology. In a rabbit model of diabetic retinopathy and wet AMD, a single intravitreal injection of GO-2301 strikingly suppressed neovascularisation, without observed toxicity. We plan running IND-enabling studies on GO-2301 in 2026. 

We are optimistic that in the near future we will see major advances in the treatment of metastatic cancer. 

Biography 

Jeff Glazier is Co-Founder and CEO of General Oncology, a clinical-stage biopharma developing therapies to overcome cancer drug resistance, including GO-4305C. He previously co-founded ProviderTech and practiced private equity law at Ropes & Gray. He holds a J.D. from Harvard Law School and an Sc.B. in Neuroscience from Brown University. 

From DDW Volume 27 – Issue 2, Spring 2026 – Read the digital issue here

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