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Risk, phenotypes, therapeutics and resistance
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With the explosion of knowledge in molecular oncology, advances are being reported almost daily in the scientific and clinical literature.
Here are some of advances in molecular oncology you may have missed during your summer vacation.
Pancreatic cancer-risk mutation
KRAS mutations are prevalent in pancreatic cancer, with over 90% of tumors harboring mutations. However, inherited susceptibility to pancreatic cancer is not conferred by germline KRAS mutations.
A novel discovery from whole-genome sequence analysis in familial pancreatic cancer revealed germline truncating mutation of the RABL3 gene. Work in zebrafish with mutated RABL3 showed increased cancer formation, and other work by the investigators showed that there is more KRAS prenylation when RABL3 is truncated through the germline mutation.
BRCA1/2-associated phenotypes
In recent years, the finding of BRCA1/2 mutations in advanced cancer has often prompted thoughts about whether a PARP inhibitor might be of use due to the tumor cell’s defective homologous recombination repair mechanisms or whether there may be a clinical trial testing it across tumor types. Mutations in these genes occur across cancer types, either somatically or in the germline, as reported by a group of researchers from Memorial Sloan Kettering Cancer Center. Jonsson and colleagues found differences in loss of the second BRCA1/2 allele and in PARP sensitivity depending on whether the genes were or weren’t predisposing to cancer. They also found that when these mutations occurred in nonBRCA1/2 cancers, they may not have contributed to the tumor development.
Phenotypic plasticity
Recent findings from single-cell RNA-sequencing of 28 glioblastoma tumors and another 401 samples from The Cancer Genome Atlas found four cellular states in glioblastoma that reflect distinct neural cell types. Interestingly, Neftel and colleagues reported a phenotypic plasticity among the four cell types that could be influenced by gene amplifications (such as CDK4, EGFR and PDGFRA loci) or mutations (eg, in NF1) that could act as genetic drivers.
BRAF-mutated cancer
We were reminded recently of the impact of targeted cancer therapy, but also its limitation, with the publication of the 5-year outcomes among 563 patients with metastatic melanoma treated in the front-line setting with the BRAF inhibitor dabrafenib (Tafinlar, Genentech) plus the MEK inhibitor trametinib (Mekinist, Novartis). The results showed 5-year DFS of 19% and OS of 34% with use of the therapy for patients with BRAF V600E- or V600K-mutated metastatic melanoma. Of note, immunotherapy had significant efficacy in the second line for this population.
In results reported at ESMO World Congress on Gastrointestinal Cancer, targeted therapy for BRAF-mutated metastatic colorectal cancer with the BRAF inhibitor encorafenib (Braftovi, Array Biopharma), MEK inhibitor binimetinib (Mektovi, Array Biopharma) and EGFR inhibitor cetuximab (Erbitux, Eli Lilly), tested in the phase 3 BEACON CRC trial, significantly prolonged OS for this difficult-to-treat patient population. This international study of 665 patients with BRAF V600E-mutant metastatic colorectal cancer and progression on two prior regimens reported median OS of 9 months vs. 5.4 months for controls, with an objective response rate of 26% with the triplet combination.
TRK inhibitor resistance
An important advance uncovered the involvement of the MAPK pathway in resistance to TRK inhibitors. A previously known mechanism of resistance involves TRK kinase domain mutations (such as acquired NTRK1 G595R). The newly uncovered mechanism involves multiple paths to MAPK pathway activation (including BRAF V600E, KRAS G12D or G12A mutations and MET amplification), and this insight was accompanied by data that MEK inhibitors plus TRK inhibitors re-establish sensitivity to TRK inhibitors in experimental models.
PD-L1 glycosylation
Researchers gained insight into anti-PD-1/PD-L1 therapeutic efficacy by recognizing that deglycosylated PD-L1 is a more reliable biomarker to guide immunotherapy. As PD-L1 is a heavily glycosylated protein, it became clear that such glycosylation could mask detection of PD-L1 expression and that incorporating deglycosylation as part of the immunostaining protocols for PD-L1 could provide a better biomarker analysis by enhancing signal and reducing false-negative PD-L1 detection.
Hyperprogression after immunotherapy
This has emerged as a hot topic because of the urgent need to identify patients whose tumors grow rapidly after immune checkpoint therapy. Tumors with MDM2 amplification or EGFR mutation have been identified as having potential for this unwanted result after immune checkpoint treatment. M2 macrophages have also been found to be associated with this result. Recently, Kamada and colleagues showed T-regs serve as an immune suppressive mechanism following anti-PD-1 therapy, and therefore may be a marker or therapeutic target.
Novel combinations
Olaparib and temozolomide. Recent data from a phase 1/phase 2 trial testing the combination of olaparib (Lynparza, AstraZeneca) and temozolomide in 48 previously treated patients with small cell lung cancer showed an ORR of 41.7%, median PFS of 4.2 months and median OS of 8.5 months. The trial included 32 xenograft models from treated patients, which recapitulated responses from the clinical trial and identified expression of inflammatory response genes as potential resistance mechanisms not only to olaparib/temozolomide, but also to etoposide/platinum.
Wee1 inhibitor adavosertib. A dose escalation trial by Cuneo and colleagues of Wee1 inhibitor adavosertib (AZD1775, AstraZeneca) in combination with gemcitabine and radiation in patients with newly diagnosed locally advanced pancreatic cancer showed promising results. Median OS for all patients was 21.7 months, and median PFS was 9.4 months. Correlative studies using hair follicle biopsies showed decreased cyclin-dependent kinase 1 (CDK1) phosphorylation as evidence of molecular target engagement.
Ibrutinib-rituximab. A phase 3 trial of 529 patients favored nonchemotherapy treatment for chronic lymphocytic leukemia involving ibrutinib (Imbruvica; Pharmacyclics, Janssen) plus rituximab (Rituxan; Genentech, Biogen) compared with chemoimmunotherapy. In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (IGHV) mutation, ibrutinib–rituximab also resulted in better 3-year PFS (90.7% vs. 62.5%).
PTC596. In preclinical studies by Eberle-Singh and colleagues using pancreatic cancer models (such as the “KPC” model), novel agent PTC596 (PTC Therapeutics), a microtubule polymerization inhibitor that doesn’t cause peripheral neurotoxicity, in combination with standard-of-care therapies, including nab-paclitaxel, appeared to overcome barriers to drug delivery and showed drug synergy.
Leflunomide. A pancreatic cancer therapy approach has sought to target mitochondrial oxidative phosphorylation (OXPHOS), which fuels tumor growth. But because this is not really tumor-specific, Yu and colleagues looked into validating and targeting mitochondrial fusion as a therapeutic target in pancreatic ductal adenocarcinoma (PDAC). They reported that normalization of mitochondrial fragmentation via fusion reduced OXPHOS and suppressed tumor growth in mouse models of PDAC. Genetic or pharmacologic inhibition of dynamin related protein-1 (DRP-1) or overexpression of mitofusin-2 (Mfn-2) did the trick. Importantly, the authors identified leflunomide, a drug used to treat arthritis, as an inducer of Mfn-2 and which could be repurposed to treat PDAC.
KRAS and tumor metabolism
Interestingly, and relevant to the above leflunomide story, RAS genes such as HRAS G12V have been shown to promote mitochondrial fragmentation through ERK phosphorylation of DRP-1. Nagdas and colleagues found that DRP-1 drives metabolic changes downstream of KRAS to promote glycolysis and transformation in PDAC. DRP-1 was suggested as a target whose loss inhibits pancreatic tumorigenesis and mitochondrial metabolism of tumor cells.
Senescence
Putting tumor cells in a state of replicative senescence has been pursued as a potential approach to treat cancer. Although not the same as killing the cells, a permanent dormant state for tumor cells can have important therapeutic consequences.
KAT6A/B inhibitors. A novel therapeutic approach that is being tested involves the idea of making cancer cells senescent through chromatin modification. Recent preclinical studies suggested that inhibitors of histone acetyltransferases KAT6A/B induce INK4A/ARF-dependent tumor cell senescence and block lymphoma tumor growth in mice.
P21 dynamics. Recent single-cell tracking studies of tumor cells identified somewhat unexpected temporal fluctuations in expression of the p21 (WAF1) cyclin-dependent kinase inhibitory protein after cellular exposure to chemotherapy. The changes in p21 expression depended on where cells were in the cell cycle when exposure to chemotherapy occurred, but even cells in a given cell cycle phase, such as G1, either increased their p21, ultimately becoming senescent, or ended up lowering their p21 and proliferating. As these fluctuations are still not completely understood, much work is needed to determine how best to exploit them in cancer therapy. However, Hsu and colleagues did suggest that checkpoint kinase 1 or ATM inhibitors, when combined with drugs such as doxorubicin, might reduce the amount of tumor cells that lowered their p21 and ultimately proliferated.
Resources
Tumor cell lines. Among the resources worth noting is a recent comprehensive transcriptomic analysis of 22 cell lines as models of primary tumors across 22 tumor types. An article by Yu and colleagues in Nature provides information to guide studies looking for representative cell lines.
Patient-Derived Models Repository. NCI has a Patient-Derived Models Repository (PDMR) that includes patient-derived xenografts, in vitro patient-derived cell cultures, cancer-associated fibroblasts and patient-derived organoids, Available at pdmr.cancer.gov, this is an incredibly valuable resource for various molecular mechanism, genomic and drug development studies across a broad range of cancer types.
P53 pathway analysis. Analysis of mutant p53 in 10,225 patient samples from 32 cancer types by Donehower and colleagues revealed that more than 91% of TP53-mutant cancers exhibit second allele loss by mutation, chromosomal deletion or copy-neutral loss of heterozygosity. Mutant TP53 RNA expression signatures correlate with poor outcomes across tumor types.
The topics in this update reflect those of broad interest to the author. Those who wish to write a guest column about cancer risk, a cancer target pathway, advances in a particular tumor type, emerging resistance mechanisms or insights into cancer hallmarks or innovative aspects of the tumor microenvironment are invited to reach out at the contact information below to arrange it.
Reference:
Baell JB, et al. Nature. 2018;doi:10.1038/s41586-018-0387-5.
Cocco E, et al. Nat Med. 2019;doi:10.1038/s41591-019-0542-z.
Cuneo KC, et al. J Clin Oncol. 2019;doi:10.1200/JCO.19.00730.
Donehower LA, et al. Cell Rep. 2019; doi:10.1016/j.celrep.2019.07.001.
Eberle-Singh JA, et al. Clin Cancer Res. 2019;doi:10.1158/1078-0432.CCR-18-3281.
Farago AF, et al. Cancer Discov. 2019;doi:10.1158/2159-8290.CD-19-0582.
Hsu CH, et al. Cell. 2019;doi:10.1016/j.cell.2019.05.041.
Jonsson P, et al. Nature. 2019;doi:10.1038/s41586-019-1382-1.
Kamada T, et al. Proc Natl Acad Sci U S A. 2019;doi:10.1073/pnas.1822001116.
Kato S, et al. Clin Cancer Res. 2019;doi:10.1158/1078-0432.CCR-16-3133.
Kopetz S, et al. Abstract LBA-006. Presented at: ESMO World Congress on Gastrointestinal Cancer; July 3-6, 2019; Barcelona, Spain.
Lee HH, et al. Cancer Cell. 2019;doi:10.1016/j.ccell.2019.06.008.
Nagdas S, et al. Cell Rep. 2019;doi:10.1016/j.celrep.2019.07.031.
Neftel C, et al. Cell. 2019;doi:10.1016/j.cell.2019.06.024.
Nissim S, et al. Nat Genet. 2019;doi:10.1038/s41588-019-0475-y.
Robert C, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1904059.
Shanafelt TD, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1817073.
Yu M, et al. JCI Insight. 2019;doi:10.1172/jci.insight.126915.
For more information:
Wafik S. El-Deiry, MD, PhD, FACP, is associate dean for oncologic sciences at Warren Alpert Medical School and director of the Joint Program in Cancer Biology at Brown University, as well as HemOnc Today’s Associate Editor for Molecular Oncology. To contribute to this column or suggest topics, email him at wafik.eldeiry@gmail.com.
Disclosure: El-Deiry reports no relevant financial disclosures.