2021 marked the 20th anniversary of the first human genome draft sequence, which led to such revolutionary landmarks as The Cancer Genome Atlas (TCGA) Program and the birth of Spatial single-cell multi-omics. We also witnessed victories against hard-to-treat drug targets, FDA approval of Amgen’s sotorasib to treat non-small-cell lung cancer, novel therapeutic strategies such as biological computers, and promising work in metastatic melanoma, fecal transplantation, and immunotherapy for pancreatic cancer. Here is a quick rundown of these advances.
Cancer-Relevant Landmarks:
1. Human Genome Project: It was twenty years ago that the first draft sequence of the human genome was reported by the International Human Genome Sequencing Consortium. This effort enabled deep and detailed analysis of genes across disease states, diverse populations and countless genomes across virtually all living organisms. This body of knowledge that we often take for granted today ushered in the powerful field of genomics which guides public health, disease diagnostics, and drug discovery and development. Our ability to sequence the COVID19 genome in less than one day is but one manifestation of the impact of this historic project.[1]
2. The Cancer Genome Atlas: Facilitated by access to the human genome sequence and enabled by large-scale genome sequencing technology and computational science, The Cancer Genome Atlas (TCGA) Program was launched 16 years ago to accelerate discoveries into the molecular basis of cancer. TCGA has since generated a comprehensive atlas of cancer-specific genetic and epigenetic changes for a wide variety of cancer types in humans and genetic model systems. This atlas has enabled researchers and physicians around the globe to understand cancer risk, detect cancer at more curable early stages, and identify new genetic aberrations leading to novel targeted therapies for specific cancers, ushering in the era of precision oncology.[2]
3. Spatial single-cell multi-omics: It is now possible to achieve high resolution profiles of the DNA, RNA and protein molecules of single cells and map the spatial juxtaposition of each cell with its neighboring cells and their profiles. This unprecedented depth of tumor profiling has revealed the cancer cell’s staggering genetic complexity and its signaling interactions with other cells in the tumor microenvironment. Such profiles are identifying symbiotic signaling circuits between cancer and host cells in the tumor microenvironment, revealing new cancer-specific vulnerabilities that can be therapeutically targeted.[3]
New Victories Against Hard-To-Treat Drug Targets:
Cancer Vaccine:
6. Vaccine trial for triple-negative breast cancer (TNBC): TNBC is the most aggressive form of the breast cancers. It is difficult to treat because it does not carry as many molecular targets responsive to current cancer treatments. Researchers have begun a Phase I trial to test a vaccine aimed at preventing the disease. The vaccine targets ɑ-lactalbumin, which is present in the majority TNBCs, and has been observed in mouse studies to position the immune system to attack emerging breast tumors.[6] Beyond this specific vaccine trial, recently proven mRNA platforms may open novel opportunities for therapy, particularly in the cancer vaccine space.
Out of the Box ‘Designer Molecules’ Could Provide New Cancer Therapeutic Strategies:
7. Biological computer: One challenge in treating cancer is targeting tumor cells without damaging the rest of the cells in the body. Researchers have discovered how to build a multi-part “programmable genetic circuit” inside a virus – essentially a nano-sized biological computer. This genetic computer can enter cancer and normal cells but the activation of its cell-killing gene requires at least two ‘on’ signals specific to cancer cells, plus the activation of an ‘off’ switch specific to normal cells. Tests in mice with liver cancer demonstrated that administration of the fully functional computer resulted in tumor eradication with minimal toxic side effects in normal tissues. The next step is to determine if such a biological computer can function in humans.[7]
Melanoma Once Again Moves the Immune Therapy Field Forward:
8. Secondary checkpoints succeed in metastatic melanoma: Melanoma research shed first light in the clinical application of checkpoint blockade inhibitors that are now used in virtually all cancer types. The latest clinical developments are the promising results of anti-LAG3 immune checkpoint inhibitors as a combination immunotherapy regimen in advanced clinical trials for melanoma. Positive outcomes were seen in the RELATIVITY-047 trial (NCT03470922) comparing nivolumab versus a combination of nivolumab plus the LAG3-targeting agent, relatlimab. At median follow-up, the combination demonstrated a statistically significant progression-free survival benefit.[8]
9. Promising bench-to-bedside progress for fecal transplantation: Fundamental research has shown that the gut microbiome plays a prominent role in many aspects of health as well as in the response to cancer treatments. Early clinical trials of fecal microbiota transplantation are eliciting improved immunotherapy responses in therapy-resistant melanoma patients. Two recent first-in-human clinical trials demonstrated that fecal transplantation from melanoma patients responsive to immune-checkpoint inhibitors into immune-checkpoint-resistant patients with metastatic disease could reverse the immune-checkpoint resistance in a subset of these transplanted patients.[9]
Hopeful Discovery in Pancreas Cancer:
10. Targeted therapy makes pancreas cancer in mice sensitive to immunotherapy: Pancreatic ductal adenocarcinoma is a major cancer killer with no effective therapies. In a series of elegant laboratory studies, a novel target – PIN1 proline isomerase – was shown to regulate many genes that fuel the growth of cancer cells and suppress anti-tumor immunity. A small molecule inhibitor targeting PIN1 rendered pancreas cancers eradicable by synergizing with immunotherapy and chemotherapy. These results are the most impressive anti-tumor activity of any drug tested to date in this pancreas cancer mouse model which recapitulates well the human disease. While clinical trials are needed, these results are unprecedented and most promising.[10]
References:
[1] International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001). Visit Source
[2] The Cancer Genome Atlas Program: Visit Source
[3] Chen, S., Teichmann, S.A. Completing the cancer jigsaw puzzle with single-cell multiomics. Nat Cancer 2, 1260–1262 (2021). Visit Source
[4] U.S. Food & Drug Administration: Visit Source
[5] U.S. Food & Drug Administration: Visit Source
[6] Cleveland Clinic Launches First-of-its-Kind Preventive Breast Cancer Vaccine Study. Cleveland Clinic Newsroom. Oct 2022. Visit Source
[7] Angelici B, Shen L, Schreiber J, Abraham A, Benenson Y. An AAV gene therapy computes over multiple cellular inputs to enable precise targeting of multifocal hepatocellular carcinoma in mice. Sci Transl Med. 13(624), eabh4456 (2021). doi: 10.1126/scitranslmed.abh4456.
[8] Robert, C. LAG-3 and PD-1 blockade raises the bar for melanoma. Nat Cancer 2, 1251–1253 (2021). Visit Source
[9] Bullman, S., Eggermont, A., Johnston, C.D. et al. Harnessing the microbiome to restore immunotherapy response. Nat Cancer 2, 1301–1304 (2021). Visit Source
[10] Koikawa K, Kibe S, Suizu F, Sekino N, Kim N, Manz TD, Pinch BJ, Akshinthala D, Verma A, Gaglia G, Nezu Y, Ke S, Qiu C, Ohuchida K, Oda Y, Lee TH, Wegiel B, Clohessy JG, London N, Santagata S, Wulf GM, Hidalgo M, Muthuswamy SK, Nakamura M, Gray NS, Zhou XZ, Lu KP. Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy. Cell 184(18), 4753-4771.e27 (2021). doi: 10.1016/j.cell.2021.07.020.