Cancer science has made incredible strides in the past decade, allowing for transformative opportunities to improve care for patients, according to Ashok Venkitaraman, MBBS, PhD, FAACR, the chair of Saturday’s Discovery Science Plenary: Novel Mechanisms Influencing Cancer Evolution.

Overall, the first Plenary Session at this year’s conference focused on factors that affect cancer evolution, beginning with a most integral tumor component: genetic mutations.

Inigo Martincorena, PhD, of Wellcome Sanger Institute, first took the audience on a tour of the “hidden world of somatic evolution in our tissues, which provides an unprecedented window into early carcinogenesis.”

In addition to investigating how factors such as alcohol and smoking influence the emergence of mutations, which can arise independently in different cells and contribute to the phenomena of somatic mosaicism and tumor heterogeneity, he revealed that while all somatic tissues accumulate mutations, genomic alterations like copy number variants are much less common, with most cells possessing stable genomes. All of these findings, he concluded, are “consistent with a multistage somatic evolution model of carcinogenesis” involving clones multiple steps away from acquiring malignant behavior.

In the realm of cancer metabolism, M. Celeste Simon, PhD, FAACR, of the University of Pennsylvania Perelman School of Medicine, explored SCARB1 as a metabolic vulnerability in kidney cancer that might also be applicable to other types of tumors. In clear cell renal carcinoma (ccRCC), she discussed how the high-density lipoprotein (HDL) receptor SCARB1 can disrupt an iron-dependent form of programmed cell death called ferroptosis, and that HDL uptake via this receptor remodels the lipidome in ccRCC. Furthermore, after pointing to data defining the critical role of SCARB1 signaling in both primary ccRCC tumor growth and metastasis, Simon showed that inhibiting SCARB1 might mitigate these malignant features as well as augment other treatments, including immunotherapy.

Coaxing cancer cells toward a less aggressive state through epigenetic mechanisms is also emerging as a potential cancer treatment approach, as demonstrated by Yang Shi, PhD, FAACR, of the Ludwig Institute for Cancer Research, in the context of leukemia. Shi shared his team’s efforts to inhibit the epigenetic regulator LSD1 along with the enzyme GSK3 involved in a wide range of biological signaling: Together, drugs inhibiting these two pathways induced robust cell differentiation in both mouse and human acute myeloid leukemia (AML) cell lines, and reduced the stemness potential of primary human AML. After detailing the distinct mechanistic impacts of the two drugs, including through patient-derived xenograft studies, Shi suggested that this approach could be an effective strategy for AML patients in the clinic.

Nicola Segata, PhD, of the University of Trento, wrapped up the session with a riveting exploration of how a better understanding of the human microbiome might enable us to improve the way we diagnose and treat cancer, including through fecal microbiota transplant (FMT).

“There is starting to be overwhelming evidence for the role of the microbiome in the response to immunotherapy,” he noted in reference to insights gained from the TACITO and FMT-LUMINate clinical trials, among others that have demonstrated how FMT can help overcome immunotherapy resistance.

“The next point will be to understand why [FMT] works and how it works because if we are able to understand which of the features are key, then we can think about next-generation biotherapeutic approaches,” Segata said. He concluded by sharing his vision of bringing about a bright future through precision microbiome approaches in oncology.