The year 2022 marked another major step in the quest to towards making cancer history. Below are several highlights among many that caught my attention and admiration. These advances rest squarely on the foundation of sustained investment in cancer research from the public and private sectors. These advances continue to save more and more lives. Just a few weeks ago the annual report from the American Cancer Society affirmed continuing declines in cancer deaths over the last 3 decades. From the highwater mark in cancer deaths in 1991, there has been a staggering 33% decline in cancer deaths. [1] This decline is based on research in cancer prevention, detection and treatment resulting in:
- Numerous public health policies such as tobacco control and HPV cancer vaccines, which prevent certain cancers;
- Increased cancer screening, such as mammograms and colonoscopy; and
- Targeted and immune therapies for many cancer types.
We must continue to invest in basic and applied research to conquer cancer because despite this progress, cancer continues to extract a heavy social, emotional and financial toll on suffering patients and their families. I am reminded of Mary Lasker’s admonition: “If you think research is expensive, try disease.”
Here are my top ten 2022 highlights. Thanks for reading.
1. Nanoparticles to treat liver cancer.
Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, exhibiting a high patient mortality rate. Using mRNA nanoparticles, researchers modified the tumor microenvironment of liver cancers by correcting a mutation in the p53 tumor suppressor. This treatment slowed the rate of tumor growth making it more responsive to immunotherapy treatment, to which most liver cancers do not respond effectively. Since p53 is mutated in many other cancers, this approach may impact the treatment of immune resistance in other cancers as well. [2]
2. Development of a p53 structural corrector.
The p53 tumor suppressor is the most frequently mutated gene in human cancer. Some p53 mutations result in mutant proteins that are unable to function as transcription factors but can still bind to DNA and block wild-type p53 activity. While mutant p53 has long been considered undruggable, there is a rare Y220C mutation found in some tumors that displays weaker DNA binding, leading to a p53 Y220C-targeted drug, PC14586. This drug binds within the mutant DNA binding domain to help restore wild-type thermal stability and gene activation. Partial responses were observed in six of 33 patients with solid tumors containing TP53-Y220C mutations. [3]
3. A treatment for “HER2-low” breast cancer.
Breast cancers can be categorized by the presence or absence of common receptor types that fuel most breast cancer growth. One such receptor is HER2. Drugs that block HER2 signaling are very effective in tumors with high HER2 expression, but these therapies were considered largely ineffective in HER2-low tumors, which constitute a large proportion of breast cancers. This year, the results of a phase 3 clinical trial was reported testing trastuzumab deruxtecan, a monoclonal antibody that targets tumor cells with low levels of HER2 expression. Results showed an 8-month increase in survival compared to physician’s choice of treatment. [4] This presentation at ASCO received a rare, sustained applause.
4. A new pancreatic cancer screening platform.
A new technology (high-conductance dielectrophoresis) is being used to develop an early detection tool to screen for pancreatic cancer, a major cancer killer. Currently, only 5% of pancreatic cancers are detected at stage 1, when early detection can yield significant health benefits. Pilot experiments on blood samples from patients were able to identify 95% of stage 1 cancers. Building on the pioneering work of the Kalluri lab [5], this new approach looks for the presence of exosomes that contain tumor proteins in blood samples to identify early tumors. Exosomes are extracellular vesicles that are part of a cell-to-cell communication system used by many cell types, including cancer cells, to deliver proteins and other subcellular particles. [6]
5. Radioligand therapy for metastatic prostate cancer.
The FDA approved pluvicto, a first-in-class targeted radioligand to treat metastatic prostate cancer patients, a group with limited treatment options. This 2-component molecule consists of a therapeutic radioisotope linked to a targeting compound that binds to the tumor. Clinical trial results showed a 35% increase in survival (11.3 vs. 15.3 months) in patients with PSMA-positive metastatic castration-resistant prostate cancer who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy. [7]
6. CAR T cell treatment for solid tumors.
CAR T cell therapy has had a major impact on the treatment of blood cancers including leukemia, lymphoma, and multiple myeloma. However, this cellular therapy has proven less successful in clinical trials for patients with solid tumors. This is primarily due to the difficulty in identifying tumor targets that are not also present and essential in vital tissues. A new target, OR2H1, an olfactory receptor protein found primarily in the nose where it aids in the perception of smell, has been found also to be expressed in a range of solid tumors. CAR T cells generated to target OR2H1 showed growth inhibition in both ovarian and lung tumors, but no measurable effect on normal cells. This advance represents an important step in developing this powerful cellular therapy for use in solid tumors, although additional barriers will need to be overcome to make this approach a new standard of care for solid tumors. [8]
7. T cell receptor gene therapy for KRASG12D pancreatic cancer.
The KRASG12D mutation is common in pancreatic ductal adenocarcinoma as well as other cancers, including non-small cell lung and colorectal cancers. A recent study in a single patient demonstrated the effectiveness of a novel T-cell receptor (TCR) gene therapy for patients with pancreatic cancer (and other cancers) that express the KRAS G12D mutation. In this study, a sample of the patient’s own T cells was modified to express two TCRs directed against mutant KRAS G12D protein. The patient, whose pancreatic cancer and metastatic lung lesions had already been treated previously with a variety of cancer drugs, responded to the treatment with marked tumor shrinkage. Although not a cure, this treatment showed a significant and durable effect in a patient who had been heavily treated with other therapies. [9] Footnote: In preclinical studies in mice, our laboratory developed an immunotherapy combination resulting in disease eradication [10], so stay tuned for clinical trials later in the year.
8. The role of the microbiome in cancer.
Cancers analyzed from various body locations have been found to contain tumor-associated fungi. In recent studies, several Candida species were highly abundant in colon tumors where they predict metastatic disease and reduced cellular adhesions, and in stomach cancers where they are linked to activation of pro-inflammatory immune pathways. Blastomyces are abundant in lung, whereas Malassezia are found in breast tumors. Such observations point to the role of fungi in cancer pathogenesis and raise the possibility of novel cancer therapeutic targets and predictive markers. [11, 12]
Breakthroughs in the treatment of melanoma.
9. Uveal melanoma: The FDA approved of the first T cell receptor (TCR) therapeutic for melanoma for use in patients with metastatic uveal melanoma. The two-part molecule combines a TCR region that recognizes tumor cells with an antibody region that binds and activates T cells. Although it has previously been demonstrated that such bi-specific T cell molecules can aid the immune system to kill cancer cells, the use of a TCR arm opens the possibility of new targets, including intracellular cancer markers. [13]
10. Dual checkpoint inhibitor combination: The FDA also approved a combination of two immune checkpoint inhibitors for the treatment of some advanced melanomas. The new therapy (opdualag) consists of a new checkpoint inhibitor, relatlimab, which blocks the LAG-3 protein found on immune cells, paired with nivolumab which blocks a different immune checkpoint protein, PD-1. Together these drugs promote an immune response against advanced or difficult to remove tumors. [14]
References.
[1] Rebecca L. Siegel, Kimberly D. Miller MPH, Nikita Sandeep Wagle MBBS, MHA, PhD, Ahmedin Jemal DVM, PhD. Cancer statistics, 2023. CA: A Cancer Journal for Clinicians. Volume 73, Issue 1 p. 17-48.
[2] Xiao Y, Chen J, Zhou H, Zeng X, Ruan Z, Pu Z, Jiang X, Matsui A, Zhu L, Amoozgar Z, Chen DS, Han X, Duda DG, Shi J. Combining p53 mRNA nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy. Nat Commun. 2022 Feb 9;13(1):758. doi: 10.1038/s41467-022-28279-8.
[3] Guiley KZ, Shokat KM. A Small Molecule Reacts with the p53 Somatic Mutant Y220C to Rescue Wild-type Thermal Stability. Cancer Discov. 2023 Jan 9;13(1):56-69. doi: 10.1158/2159-8290.CD-22-0381.
[4] Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690.
[5] Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020 Feb 7;367(6478):eaau6977. doi: 10.1126/science.aau6977.
[6] Hinestrosa JP, Kurzrock R, Lewis JM, Schork NJ, Schroeder G, Kamat AM, Lowy AM, Eskander RN, Perrera O, Searson D, Rastegar K, Hughes JR, Ortiz V, Clark I, Balcer HI, Arakelyan L, Turner R, Billings PR, Adler MJ, Lippman SM, Krishnan R. Early-stage multi-cancer detection using an extracellular vesicle protein-based blood test. Commun Med (Lond). 2022 Mar 17;2:29. doi: 10.1038/s43856-022-00088-6
[7] U.S. Food & Drug Administration: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer.
[8] Martin AL, Anadon CM, Biswas S, Mine JA, Handley KF, Payne KK, Mandal G, Chaurio RA, Powers JJ, Sprenger KB, Rigolizzo KE, Innamarato P, Harro CM, Mehta S, Perez BA, Wenham RM, Conejo-Garcia JR. Olfactory Receptor OR2H1 Is an Effective Target for CAR T Cells in Human Epithelial Tumors. Mol Cancer Ther. 2022 Jul 5;21(7):1184-1194. doi: 10.1158/1535-7163.MCT-21-0872.
[9] Leidner R, Sanjuan Silva N, Huang H, Sprott D, Zheng C, Shih YP, Leung A, Payne R, Sutcliffe K, Cramer J, Rosenberg SA, Fox BA, Urba WJ, Tran E. Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer. N Engl J Med. 2022 Jun 2;386(22):2112-2119. doi: 10.1056/NEJMoa2119662.
[10] Gulhati P, Schalck A, Jiang S, Shang X, Wu CJ, Hou P, Ruiz SH, Soto LS, Parra E, Ying H, Han J, Dey P, Li J, Deng P, Sei E, Maeda DY, Zebala JA, Spring DJ, Kim M, Wang H, Maitra A, Moore D, Clise-Dwyer K, Wang YA, Navin NE, DePinho RA. Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1/CXCR2 results in antitumor immunity and durable response in pancreatic cancer. Nat Cancer. 2022 Dec 30. doi: 10.1038/s43018-022-00500-z.
[11] Dohlman AB, Klug J, Mesko M, Gao IH, Lipkin SM, Shen X, Iliev ID. A pan-cancer mycobiome analysis reveals fungal involvement in gastrointestinal and lung tumors. Cell. 2022 Sep 29;185(20):3807-3822.e12. doi: 10.1016/j.cell.2022.09.015.
[12] Narunsky-Haziza L, Sepich-Poore GD, Livyatan I, Asraf O, Martino C, Nejman D, Gavert N, Stajich JE, Amit G, González A, Wandro S, Perry G, Ariel R, Meltser A, Shaffer JP, Zhu Q, Balint-Lahat N, Barshack I, Dadiani M, Gal-Yam EN, Patel SP, Bashan A, Swafford AD, Pilpel Y, Knight R, Straussman R. Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions. Cell. 2022 Sep 29;185(20):3789-3806.e17. doi: 10.1016/j.cell.2022.09.005.
[13] Kingwell K. T cell receptor therapeutics hit the immuno-oncology stage. Nat Rev Drug Discov. 2022 May;21(5):321-323. doi: 10.1038/d41573-022-00073-7.
[14] Amaria RN, Postow M, Burton EM, Tezlaff MT, Ross MI, Torres-Cabala C, Glitza IC, Duan F, Milton DR, Busam K, Simpson L, McQuade JL, Wong MK, Gershenwald JE, Lee JE, Goepfert RP, Keung EZ, Fisher SB, Betof-Warner A, Shoushtari AN, Callahan M, Coit D, Bartlett EK, Bello D, Momtaz P, Nicholas C, Gu A, Zhang X, Korivi BR, Patnana M, Patel SP, Diab A, Lucci A, Prieto VG, Davies MA, Allison JP, Sharma P, Wargo JA, Ariyan C, Tawbi HA. Neoadjuvant relatlimab and nivolumab in resectable melanoma. Nature. 2022 Nov;611(7934):155-160. doi: 10.1038/s41586-022-05368-8.