A Cancer Researcher's Reflections on the Revolution in Oncology
When I first stepped into a cancer research laboratory in the early 1970s, the landscape of oncology was fundamentally different. We had only three main weapons against cancer: surgery, radiation, and crude chemotherapy that attacked both cancerous and healthy cells with devastating collateral damage. Back then, we understood cancer as a black box—we knew it grew uncontrollably and killed people, but the intricate molecular mechanisms remained largely mysterious. The National Cancer Act had just been signed in 1971, unleashing unprecedented resources and declaring a "War on Cancer" that would shape my entire career 1 .
Over the past five decades, I've witnessed a revolution—not just in treatments, but in our very understanding of what cancer is. From the early days of non-specific cytotoxic agents to today's sophisticated immunotherapies and targeted treatments, the journey has been longer and more complex than any of us initially imagined. This is the story of how we progressed from blindly bombing cancer to precisely engineering its destruction, a transformation that represents one of the most remarkable scientific evolutions in modern medicine.
The survival rate for many cancers has doubled since the 1970s, with childhood leukemia survival increasing from less than 10% to over 90% for some types.
The most profound change I've witnessed has been the fundamental shift in how we conceptualize cancer. In my early career, we largely viewed cancer through a histological lens—classified by the tissue where it originated. The treatment approach was similarly simplistic: cut it out, burn it with radiation, or poison it with chemicals.
The turning point came when we began understanding cancer at the molecular level. Instead of seeing cancer as an invader to be eliminated, we started recognizing it as a complex biological system that had hijacked normal cellular processes. This shift from anatomical to molecular classification represented the true beginning of modern oncology.
Identification of first oncogenes; Tamoxifen approved for breast cancer 1 . This marked the foundation for targeted therapy and the first endocrine therapy.
HER2 oncogene discovered; HPV linked to cervical cancer 1 . This advanced our understanding of cancer drivers and established viral causation.
BRCA1/2 genes cloned; First targeted monoclonal antibodies approved 1 . This enabled genetic risk identification and marked the beginning of immunotherapy.
First targeted therapies (imatinib); Cancer genome sequencing begins. This represented a paradigm shift to molecular targeting.
CAR-T cell therapy approved; Checkpoint inhibitors revolutionize treatment 2 . This introduced effective immunotherapies for both solid and blood cancers.
The story begins with understanding two key pathways for DNA repair in cells: one involving the PARP (Poly ADP-ribose polymerase) enzyme that repairs single-strand DNA breaks, and another involving BRCA1 and BRCA2 proteins that repair double-strand breaks through homologous recombination.
Cancer cells with BRCA mutations already have compromised double-strand break repair. When we inhibit PARP in these cells, single-strand breaks accumulate and become double-strand breaks during DNA replication. These double-strand breaks become fatal for BRCA-deficient cancer cells—a concept called synthetic lethality.
The PETRA trial, led by Dr. Timothy Yap at MD Anderson, evaluated a next-generation PARP inhibitor called saruparib that selectively targets PARP1 only 2 . This selectivity was designed to maintain efficacy while reducing toxicity.
| Parameter | First-Generation PARP Inhibitors | Next-Generation Saruparib |
|---|---|---|
| Target Specificity | PARP1 & PARP2 | PARP1-selective |
| Efficacy in HRR-deficient cancers | Strong | Encouraging, with similar efficacy |
| Common Side Effects | Hematologic toxicity, fatigue, nausea | Improved safety profile |
| Therapeutic Window | Moderate | Enhanced |
| Clinical Status | Approved for multiple indications | Phase III trials ongoing |
Recent research from Dr. Boyi Gan's lab has identified a potential strategy to overcome PARP inhibitor resistance in BRCA1-deficient cancers. Their work revealed that co-inhibition of GPX4—a protein that inhibits ferroptosis (an iron-dependent form of cell death)—could resensitize resistant tumors to PARP inhibition 2 .
Circulating tumor DNA (ctDNA) blood tubes; Targeted NGS panels 3 . Used for liquid biopsies and monitoring treatment response.
3D tumor spheroids; Organoids; ALDEFLUOR cancer stem cell detection 4 . Enables better disease modeling and studying tumor heterogeneity.
Multi-functional microplate readers; High-throughput screening systems 3 . Used for drug screening and automated experimentation.
Saliva/buccal DNA kits; Stool stabilization kits 3 . Used for genetic risk assessment and microbiome studies.
Machine learning algorithms; Bioinformatics platforms. Used for pattern recognition and predictive modeling in cancer research.
One of the most important evolutions in my field has been the emphasis on translational research—the process of moving discoveries from the laboratory to clinical applications. Early in my career, basic research and clinical practice often existed in separate silos. Today, they're integrally connected.
The traditional model of "bench to bedside" has been rightly critiqued as sometimes too linear. A more effective approach cycles between bedside to bench and back again: we make observations in patients, take those questions to the laboratory, develop solutions, and test them in patients again 5 . This iterative process has proven much more efficient for therapeutic development.
Trials that can modify parameters based on interim results, making the research process more efficient.
Enroll patients based on molecular alterations rather than tumor type, allowing for more targeted approaches.
Studies that minimize bias by keeping both participants and researchers unaware of treatment assignments 6 .
Evaluate treatments before surgery, allowing assessment of biological effects on the tumor.
We're increasingly focused on intercepting cancer before it becomes invasive, through better screening, risk assessment, and preventative therapies. The development of cancer vaccines like ELI-002, which targets KRAS-mutated pancreatic and colorectal cancers, shows promise in preventing relapse 2 .
Our understanding of how the gut microbiome influences cancer development and treatment response is exploding. The BE GONE trial showed that simply adding one cup of beans to the daily diet of colorectal cancer survivors could positively influence their gut microbiome, reducing inflammatory pathways 2 .
We're developing sophisticated strategies to combat resistance, such as the combination of PARP and GPX4 inhibition mentioned earlier, and CD28 costimulation to enhance CAR NK cell persistence and efficacy 2 .
Fifty years ago, we faced cancer with limited tools and understanding. Today, we have an arsenal of targeted therapies, immunotherapies, and sophisticated diagnostic tools that have transformed outcomes for many cancers. The survival rate for childhood cancers has improved dramatically, and many adults with cancer are living longer, better lives.
Yet the revolution remains unfinished. Too many cancers still lack effective treatments, and too many patients still suffer from our therapies. The next generation of cancer researchers—equipped with tools we couldn't have imagined—will need to address these challenges with both scientific rigor and compassionate innovation.