Promising biomarkers for improving non-small cell lung cancer treatment

Nancy Guo

Lung cancer remains the leading cause of cancer-related deaths in the world, and non-small cell lung cancer (NSCLC) accounts for 84% of lung cancer cases and almost 80% of lung cancer deaths. There are currently no effective biomarkers to select chemotherapy, immunotherapy, and radiotherapy for treating lung cancer patients. Novel therapeutic strategies are needed to combat this deadly disease. Our previous study developed a 7-gene assay for NSCLC prognosis and prediction of chemotherapeutic benefits. The ability of this gene assay to identify those at high risk for recurrence or metastasis would potentially inform the selection of specific adjuvant chemotherapy for these patients. Multiple identified genes were associated with chemoresponse and radiotherapy response in NSCLC. Included in this 7-gene assay, CD27 and ZNF71 had concordant mRNA and protein expression in NSCLC tumors. Our recent study showed that ZNF71-KRAB, the KRAB isoform that is transcriptional repression, was associated with epithelial-to-mesenchymal transition (EMT) in NSCLC tumors and cell lines. CD27, an emerging immune-checkpoint inhibitor, is being tested as adjuvant therapy in phase I/II clinical trials for multiple tumor types with promising results. These biomarkers have the potential to select chemotherapy, immunotherapy, and radiotherapy in combination with patient demographic, clinical, pathological, and comorbid characteristics using the prognostic model we developed (http://www.personalizedrx.org/) to achieve the goals of precision oncology.

 

Prostatic cancers cases being treated with MDB method

GIUSEPPE DI BELLA

Stable and objective remission of 12 prostate cancer patients treated only with The Bella Method (MDB)
OBJECTIVE: To evaluate the objective clinical, biochimical and metabolical response and the safety of the combined administration of Di Bella Method (DBM) in patients with a histological diagnosis of prostate adenocarcinoma.
MATERIALS AND METHODS: Twelve patients with a certain diagnosis of prostate cancer and with measurable disease characteristics were evaluated according to the RECIST criteria. The 12 patients had not been previously operated on or chemo-radiotreated. After giving informed consent, they voluntarily accepted the administration of the treatment as first-line therapy.
In detail, they were administered in the following ways:
• All-trans retinoic acid solution (ATRA, 1543488.372 IU), axerophthol palmitate (909000 IU), beta-carotene (3334000 IU) in alpha tocopheryl acetate (1000000 IU), in a stoichiometric ratio of 1: 1: 4: 2; 2-3 in conjunction with
• Dihydrotachisterol (cholecalciferol-Vit.D3, ATITEN ©; 15200 IU);
• Somatostatin: scalar administration;
• Tetracosactide (Synachten® – synthesis ACTH) with frequent monitoring of blood pressure and blood sugar;
• Octreotide LAR (slow release) 30 mg intramuscular;
• Enantone 3.75mg intramuscolar;
• Bicatulamide (Casodex®) 50 mg;
• Melatonin 5 mg;
• Cabergoline 0.25 mg;
• Bromocriptina® 2.5 mg;
• Cyclophosphamide® (from 50 mg to 75mg) gradual dosage;
• Ascorbic acid (Vit C) gradual dosage, with
• Carbonate calcium 500 mg in the same glass;
• Chondroitin sulfate 250 mg + Glucosamine 250 mg;
• Sideral;
• Calciolevofolinate 22 mg
RESULTS AND CONCLUSIONS: This preliminary study shows that all 12 patients not previously treated by surgery and/or chemo-radiotherapy, can achieve a more than positive clinical benefit and they alla achieved a five-year stable objective clinical instrumental, metabolic, biochemical complete remission with DBM applied as first-line therapy. Further clinical inestigations are recommended.

 

Immunostimulatory gene therapy for pancreatic cancer – from preclinic to clinic

Angelica Loskog

Pancreatic cancer is a devastating disease with poor overall survival. Pancreatic cancer is not only resistant to conventional chemotherapy but also to the novel toolbox of checkpoint blockade antibodies. Resistance to checkpoint immunotherapy is likely due to the low presence of tumor-infiltrating T cells which in turn depends on a low mutational burden and high infiltration of immunosuppressive myeloid cells among other immune escape mechanisms. Our goal is to inflame the tumor microenvironment by immunostimulatory gene therapy to kick-start anti-tumor responses via increased antigen presentation and subsequent activation of both T and NK cells. We are utilizing and oncolytic adenovirus encoding a human designed trimerized, membrane-bound CD40L and full length 4-1BBL (LOAd703) for gene transfer. The mechanism of action and preclinical work leading to clinical lead selection will be discussed. Further, preliminary results from ongoing clinical trials will be presented including safety, response data and biopsy proteomics.

 

Better understanding the role of PARP inhibitors in triple-negative breast cancer

Saima Hassan

Breast cancer is the most common cancer in women. Triple-negative breast cancers (TNBCs) lack expression of hormone receptors and HER2, have an earlier onset of recurrent disease, and a shorter overall survival. Potent PARP inhibitors (PARPi) such as talazoparib and olaparib, are orally available therapeutics that target DNA repair, and have demonstrated efficacy in breast cancer patients with mutations in BRCA1/2 (BRCA-MUT) in the metastatic and adjuvant settings. Clinical trials have tested the combination of a low potency PARPi (veliparib) with carboplatin. It would be ideal we could better select a TNBC patient subpopulation that could best benefit from PARPi. Furthermore, it is plausible that more potent PARPi can be used in combination with carboplatin to inhibit the development of distant metastasis for these hard-to-treat cancers.
To better select which TNBC patients will benefit from PARPi, we have derived a 63-gene signature. Using a panel of TNBC cell lines, we quantified the 53BP1 response (marker of double-strand breaks) of three PARPi, veliparib, olaparib, and talazoparib using single-cell analysis. We then categorized our cell lines as sensitive or resistant and created a fold-change gene expression metric that was applied to the entire transcriptome. In combination with a curated gene list associated with PARPi or DNA damage response, we performed a gene set and pathway enrichment analysis, to identify statistically significant pathways with 63 associated genes. Using a previously published cohort of 7 PDX tumors, we found that our gene signature predicted response to olaparib with a high overall accuracy of 86%. We also identified our gene signature amongst 45% of untreated TNBC patients.
To better understand the combination of a potent PARPi, talazoparib and carboplatin, we determined that their combination resulted in a synergistic effect in 9/10 TNBC cell lines. We compared concomitant talazoparib and carboplatin, sequential talazoparib then carboplatin (seq TC), and sequential carboplatin followed by talazoparib in a BRCA wild-type TNBC MDAMB231 cell line and orthotopic xenograft. Paradoxically, we found that the seq TC approach demonstrated the greatest reduction, 70.4% (P<0.0001) in cell migration, 76.3% in liver metastasis (P = 0.02), and 56.4% in lung metastasis (P < 0.0001). Taken together, it is plausible that PARPi will be effective amongst a larger TNBC subpopulation, of which our 63-gene signature could be used a tool for improved selection. Furthermore, the use of PARPi in combination with carboplatin is an effective approach which can be used to inhibit the development of metastatic disease.

 

Liquid Biopsies Using Circulating Tumor DNA in Non-Small Cell Lung Cancer

Aadel Chaudhuri

Liquid biopsy technologies are revolutionizing our ability to detect cancer earlier and more precisely, and are poised to enable more personalized response-adapted cancer treatment. Here we analyzed plasma cell-free DNA of patients with NF1-associated malignant peripheral nerve sheath tumor (MPNST) vs. its benign precursor lesion (plexiform neurofibroma) via low-pass whole genome sequencing. We performed cell-free DNA fragment size and copy number analysis and determined that patients with MPNST have shorter cell-free DNA fragment sizes and greater copy number alterations than patients with benign plexiform neurofibroma. These properties enabled us to accurately distinguish patients with MPNST from those harboring only the benign precursor lesion. We separately performed urine cell-free DNA analysis from patients with muscle-invasive bladder cancer, and identified molecular residual disease (MRD) after neoadjuvant chemotherapy but before surgery in a subset of patients. These patients had superior survival outcomes, and urine-derived MRD performed favorably compared to gold-standard pathological response assessment of the surgical specimen. The liquid biopsy technologies described herein have the potential to enable more personalized and precise management of patients and improve clinical outcomes through earlier cancer detection.

Bridging the gap: incorporating exercise evidence into clinical practice in breast cancer care

Jenna Smith-Turchyn

Regular participation in exercise significantly improves physical, psychological, and quality of life outcomes in cancer survivors. Preliminary observational evidence also suggests regular exercise can prevent recurrence and mortality in some cancers. North American guidelines suggest cancer survivors participate in 90-150 minutes of moderate-vigorous aerobic exercise each week and twice weekly strength training for all major muscle groups. However, only a small portion of cancer survivors participate in regular physical activity and many participation barriers exist for survivors related to knowledge and accessibility. This presentation summarizes background information on exercise for cancer survivors and highlights recent work in three areas of oncology rehabilitation: novel exercise implementation strategies for cancer survivors, involving ‘hard to reach’ cancer populations in exercise, and using peer-based exercise programs to facilitate exercise behavior. Together content described in this presentation can be used by clinicians and researchers when devising exercise-related interventions for survivors of cancer.