While we live in an era where cancer is increasingly managed, certain types of cancers still bring frustration to patients. There are many refractory (hard-to-treat) cancers that are difficult to detect early, challenging to surgery, or prone to recurring even after treatment. However, the possibilities of treating these cancers are recently expanding. Thanks to a flood of cutting-edge treatments emerging across diagnosis, surgery, chemotherapy, and radiation therapy, and particularly because artificial intelligence (AI) is dramatically accelerating drug discovery, a strong tailwind is boosting the conquest of hard-to-treat cancers. We explored the evolution of cancer treatments and the forefront of refractory cancer therapies with Professor Park Kyung-hwa of Korea University Anam Hospital's Department of Hematology-Oncology and Jung Hee-jin, Director of the Korea University College of Medicine Vaccine Innovation Center.

Cytotoxic - Targeted - Immunotherapy

Cancer diagnosis has evolved from visually confirming tumors to decoding cell morphology, protein molecules, and gene sequences. Cancer treatment has historically gone through processes of surgery, chemical/radiation chemotherapy, and recurrence tracking examinations. Professor Park noted, "When pain did not disappear even after removing the tumor mass, the necessity of medical treatment was recognized, and the development of molecular biology unraveled cancer mechanisms. Over the past century, cancer diagnosis and treatment have made dazzling progress."

The first medical treatments were born during World War II. Cytotoxic anticancer drugs were invented based on the observation that mustard gas lowers white blood cell counts. While effective, their limitations were distinct: they indiscriminately attacked fast-dividing cells, resulting in cascading side effects such as vomiting and hair loss.

Immunotherapies, designed to complement this, sprouted from molecular biology. In the 1980s and 1990s, the discovery that unlimited proliferation is driven by specific gene mutations opened the way to precisely target only cancer cells. Next-generation sequencing (NGS) technology, which emerged in 2010, added fuel to the development of targeted therapies.

Targeted anticancer drugs also hit a wall: drug resistance. Scientists turned their attention to the immune system. The reasoning was: "Cancer cells trick immune cells to block attacks; what if we block these decoy brakes (such as PD-1 and CTLA-4)?" Based on this idea, the first immunotherapy drug, 'Yervoy,' was born in 2011.

Immunotherapies do not cause side effects like vomiting or hair loss, and because immune cells remember how to fight cancer, long-term survival (cure) can be expected even after stopping the medication. They are currently used as primary standard treatments for dozens of types of cancer, including stomach cancer, lung cancer, and kidney cancer.

The three major pillars of anticancer therapeutics continue to evolve through second and third generations. Research into combining these treatments is also active. Antibody-drug conjugates (ADCs), which combine targeted therapy and immunotherapy to hunt down cancer cells and detonate drugs exclusively inside them, are a prime example. Professor Park stated, "ADCs have recently shown high efficacy in metastatic breast cancer, colorectal cancer, and more. Technologies targeting both cancer gene mutations and immune evasion pathways are narrowing the limitations of conventional treatments one by one."

Personalized mRNA Cancer Vaccines

The most spotlighted field recently is cancer vaccines. Their concept differs from hepatitis B or cervical cancer (HPV) vaccines, which prevent causative viruses. The principle is to introduce mutant proteins unique to cancer cells into the immune system so they are recognized as "enemies," placing weight on treatment and recurrence prevention.

Visible results are also emerging. Recently, American pharmaceutical companies Moderna and Merck announced Phase 3 clinical trial results showing that personalized messenger ribonucleic acid (mRNA) cancer vaccines reduced the risk of recurrence and death in high-risk melanoma patients after surgery by 42%. However, differing treatment efficacy across cancer types and the hundreds of millions of won required for 1-to-1 customized manufacturing remain hurdles to solve.

Director Jung explained, "Currently, they are most likely to be introduced first to patient groups with high postoperative recurrence risk, identifiable targets, and maintained immune function. While potential is also visible in pancreatic and kidney cancers, it is still at an early research stage."

Radiation therapy has similarly advanced to a level of tracking tumor movement for precise targeting. Proton therapy, known as the "dream radiation," is at the center of this. Accelerated proton particle beams are designed to concentrate energy the moment they reach the cancer tissue and then stop, making them particularly useful for treating brain tumors, pancreatic cancer, and others located close to major organs.

Multi-cancer early detection (MCED), which finds signs of over 50 types of cancer with a single drop of blood, and minimally invasive robotic surgery are also drawing attention. Although still a supplementary tool, MCED makes it possible to detect cancers that previously lacked proper regular screening methods, such as pancreatic cancer or ovarian cancer, early on. Robotic surgery, performed through a single incision, significantly eases the recovery burden for patients.

The Path to Conquering Refractory Cancers

As an era of precision treatment unfolds—where cause identification, ultra-fast diagnosis, and personalized therapy connect into a single stream—refractory cancers are also finding a breakthrough for treatment.

Pancreatic cancer is difficult to detect early, meaning surgical resection is often impossible at the time of diagnosis. However, neoadjuvant chemotherapy—administering complex anticancer drugs like 'FOLFIRINOX' in advance to shrink the tumor before attempting surgery—is recently being utilized. Targeted therapies have also achieved results. In August, the US Food and Drug Administration (FDA) approved 'Rasonque' (generic name: darasertrasib), a pancreatic cancer treatment developed by biotech firm Revolution Medicines. Rasonque attacks the RAS gene—which drives pancreatic, liver, and colorectal cancers—to shrink and eliminate cancer cells. In a clinical trial involving 500 adult patients with previously treated metastatic pancreatic cancer, the median overall survival was approximately 13.2 months, nearly double compared to conventional treatments (6.7 months). Median overall survival refers to the survival duration of the patient located exactly in the middle when all patients are lined up sequentially.

Precision treatment is also becoming a reality in the field of malignant brain tumors, which are prone to frequent recurrence. In August 2024, the FDA approved 'Vorasidenib,' a targeted therapy developed for glioma patients harboring IDH1 gene mutations. Clinical results showed that the period during which patients took the drug and maintained daily life without disease progression was more than double (27.7 months) compared to the placebo group (11.1 months).

Treatments for malignant brain tumors (glioblastoma), which have an average survival period of around one year, are also making progress. Chimeric antigen receptor T-cell (CAR-T) therapies—which genetically modify a patient’s own immune cells outside the body so they precisely attack cancer cells before reinfusing them—have opened up treatment possibilities. Ovarian cancer is also meeting positive changes with the advent of 'Avastin,' which suppresses the formation of blood vessels in cancer cells to cut off nutrient supplies, and 'PARP inhibitors,' which precisely target BRCA gene mutations.

The Future of Cancer Treatment

Oracle founder Larry Ellison recently predicted, "Thanks to AI, most cancers will disappear within 5, or at latest 10, years." Medical professionals agree, "Because cancer is a complex disease intertwined with long-term lifestyle and environmental factors, it is premature to pinpoint a cure date," but they add, "Before long, with the help of AI, we will be able to immediately design personalized therapeutics and proactively block drug resistance."

In reality, AI is transforming the paradigm of drug development and therapeutic platforms. A representative technology involves growing a patient's cancer cells outside the body into 3D mini-organs and tracking drug responses using AI to preemptively filter out side effects. Research on 'Medical Digital Twins,' which test tens of millions of drugs in a virtual space inside a computer, is also active. Similar to the pancreatic cancer 'Molecular Twin' platform at Cedars-Sinai Medical Center in the US, this approach trains AI on a patient's genetic and protein information to build a virtual model that reacts identically to actual cancer cells, predicting the optimal treatment method.

Research where AI predicts cells and signaling pathways with a high likelihood of showing drug resistance is also active. Much like reading an opponent's next move in chess or Go, clinical research where AI preemptively predicts the evolutionary direction and resistance-onset pathways of cancer cells to block them proactively is getting underway, centered around major cancer research institutes.

[ⓒ Global Economic Times. 무단전재-재배포 금지]