Pancreatic ductal adenocarcinoma (PDAC) is one of the most common and aggressive forms of pancreatic cancer that has remained difficult to diagnose early and treat successfully. PDAC has a five-year survival rate below 10% and is one of the leading causes of cancer death. Complete surgical resection is one of the few curative treatment modalities, and chemotherapy protocols have limited efficacy.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most common and aggressive forms of pancreatic cancer that has remained difficult to diagnose early and treat successfully. PDAC has a five-year survival rate below 10% and is one of the leading causes of cancer death. Complete surgical resection is one of the few curative treatment modalities, and chemotherapy protocols have limited efficacy.
Unfortunately, most existing immunotherapy-based treatments are also associated with poor response rates. Recent analyses of PDAC samples have provided critical insights into genetic alterations that drive tumorigenesis and have identified potential therapeutic targets. Here we highlight several of these key findings and how they may lead to advances in PDAC treatment.
PDAC arises in the epithelial cells of pancreatic duct, or ductules, and is thought to progress in a manner like other carcinomas, in which the normal epithelial cells transition into pre-invasive pancreatic intraepithelial neoplasia lesions that eventually form invasive PDAC. Most PDAC tumors carry somatic mutations in oncogenes, particularly KRAS, TP53, CDKN2A, and SMAD4. KRAS mutation is the most frequent event in PDAC. The assumption that KRAS is an undruggable target based on extensive drug screens that showed in vitro inhibition but limited or no efficacy in animal models is finally being challenged by the very promising results obtained by administration of Sotoresib (KRAS p.G12C inhibitor) in patients with advanced pancreatic cancer (NCT03600883), and by the identification of small-molecules that inhibit KRAS p.G12D in preclinical studies[6,7].
The need for druggable targets or biomarkers for PDAC has led to more innovative approaches to identify unique molecule attributes. A recent comprehensive proteogenomic characterization of PDAC pancreatic ductal tissues compared against paired normal adjacent tissue, and the findings validated known mutations in oncogenes. This study also defined previously unknown genomic alterations and analyzed differences in protein expression and protein phosphorylation status between tissues. This comprehensive analysis identified a panel of proteins linked to early stage PDAC, and phosphoproteomic analysis identified several signaling pathways downstream of KRAS, including PI3K/AKT/mTOR and MAPK/ERK, that may be targeted by existing kinase inhibitors. The PAK1/PAK2 kinases were also identified as dysregulated in PDAC tissues and have the potential to be targeted therapeutically.
Recent studies have also better characterized the tumor microenvironment (TME) of PDAC and how this may limit treatment efficacy. PDAC tumors tend to be highly heterogenous with a dense stroma and disorganized blood vessels, which impair drug penetration. The TME is enriched for myeloid derived suppressor cells and regulatory T cells and displays a low mutational burden, thus making this a “cold” tumor immunophenotype that is resistant to existing immunotherapies. Current studies are examining immunotherapy or drug-based strategies to turn “cold” PDAC tumors into “hot” tumors that would be receptive to immune checkpoint blockade.
Further advances in PDAC research will require similar extensive proteogenomic studies that better define dysregulated pathways that trigger early events in tumor formation and may function as early biomarkers for disease. The search for novel therapeutic targets or combinations of targets is also essential to improving the currently dismal array of treatment options for PDAC patients. Champions Oncology has 81 highly characterized Pancreatic Cancer Models available for preclinical studies, click below to learn more about how these models can propel your research.
Lung cancer is an aggressive malignancy that correspond to approximately 12% of newly diagnosed cases per year and that remains one of the leading causes of cancer-related deaths (21%). Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and is typically diagnosed at advanced stages.
Extensive genomic studies of NSCLC have been essential to identifying mutations that drive oncogenesis and has been critical to the development of targeted therapies. Here we highlight progress in NSCLC treatment and identify areas of ongoing research.
For decades, chemotherapy was the primary treatment for NSCLC, and platinum-based chemotherapies are still used today in combination with radiotherapy and targeted therapies. Platinum-based chemotherapies have been improved since their initial development in the late 20th century, and “platinum doublets” or “triplets”, which combine two or three different platinum-based cytotoxic compounds, have been shown to better target NSCLC and cause less toxicity. Chemotherapy is still used as a first line treatment for advanced NSCLC, but overall effectiveness is limited when used alone. Advances in targeted therapies and immune checkpoint blockade have greatly enhanced the effectiveness of chemotherapy on overall survival and progression-free survival.
Genetic analysis of NSCLC tumors has led to the use of targeted therapies. Mutations in the epidermal growth factor receptor (EGFR) were identified as the most prevalent defect in NSCLC patients across genders, ethnic groups, and smoking status. Several common mutations have been characterized, but numerous rare mutations have also been identified, and most of these mutations target the tyrosine kinase domain, which results in unchecked cellular proliferation due to engagement of downstream MAKP, PI3K, and STAT signaling pathways. First (gefitinib and erlotinib) and second (afatinib and dacomitinib) generation tyrosine kinase inhibitors (TKIs) have been approved by the FDA to treat EGFR-mutated NSCLC. Unfortunately, treatment resistance and disease recurrence occur at a very high rate, and these TKIs are also associated with significant toxicity and undesirable side effects that result in adjustments of treatment regimens. Third generation TKIs (e.g. osimertinib) that target specific EGFR mutations associated with acquired resistance to first and second generation TKIs have been approved and have been very successful in treating EGFR-mutated NSCLC as a first or a second line treatment. Because resistance to third generation TKIs eventually also arises, fourth generation TKIs are currently under development or are being used in ongoing clinical trials. Many of these next generation inhibitors have been carefully designed to optimize target specificity and reduce adverse events frequency and severity. Mutations in other genes have also been observed at low frequency in NSCLC, and several clinical trials are now evaluating targeted therapies with inhibitors that target these genes, including, ALK, MET, ROS1, and BRAF among others[7, 8]. Capmatinib, an inhibitor targeting METex14 mutation, and adagrasib and sorotasib, both targeting KRAS G12C mutation, have recently been granted approval for treatment of NSCLC tumors presenting with the corresponding mutation[9, 10, 11]. In addition to small molecule inhibitors, Antibody-Drug Conjugates (ADC), a class of anti-cancer therapy capable of transporting cytotoxic drugs directly to tumor cells, are currently developed against NSCLC antigenic targets.
Immunotherapies that target the immune checkpoint molecules like Programmed Death (PD)-1 or its ligand PD-L1 have been shown to have therapeutic effects as second-line treatments in combination with chemotherapy for patients lacking mutations that can be treated with approved targeted therapies. While several of these trials have shown improvements in overall survival, serious adverse events have also been elevated. In addition to immune checkpoint targeting, other immunotherapies are currently under development, and a bispecific antibody has been recently approved for the treatment of a subset of NSCLC patients.
The availability of oncogenic driver mutations and of immune checkpoint targeted therapies have revolutionized NSCLC treatment and require the concomitant development of diagnostic tools to stratify patients and maximize the efficacy of these therapeutic options . Oncogenic mutations are usually good companion biomarkers to indicate a patient as eligible to receive the associated treatment, however, diagnostic strategies need to be implemented to monitor patient response and anticipate or detect acquired resistance as early as possible. Immune checkpoint proteins are also currently tested as biomarkers to stratify patient, as an example a PD-L1 diagnostic test has been recently approved by FDA as companion biomarker to identify patients who are candidates for adjuvant treatment with atezolizumab .
Advances in NSCLC have shifted the median overall survival from 2-4 months in the 1960s to more than 2 years since advent chemotherapy combined with immunotherapy or targeted inhibitors in the 2010s. Our deeper understanding of mutations that drive NSCLC and our ever-expanding arsenal of targeted therapies or immune modulators will further improve survival and quality of life for NSCLC patients.
Hepatocellular carcinoma (HCC) is one of the most prevalent types of liver cancer, and it usually develops in patients with underlying cirrhosis or chronic liver disease and metabolic syndrome. HCC can spread to other body parts and affect patients' survival rates and outcomes severely. In this blog post, we will provide essential insights into HCC metastases and delve into the therapeutic options.
Over 60% of patients with HCC are diagnosed in advanced stages, leading to an overall 5-year survival rate of 21%. However, this rate is between 60% and 70% in patients with early diagnosis who undergo liver transplants. Patients diagnosed with advanced-stage HCC, defined by the presence of vascular invasion or extrahepatic metastases, have a poor prognosis with a median survival of less than 1 year.  Early detection of HCC is vital in increasing therapeutic opportunities and improving patients’ outcomes, and new diagnostic biomarkers are under investigation to enhance HCC screening.
Available treatments for HCC metastases depend on the tumor's location, the extent of the cancer, and the patient's general condition. Surgical resection, liver transplant, radiofrequency, and microwave ablation are all first-line treatments for tumors that have not spread to other body parts. Chemoembolization is commonly used and improves survival in asymptomatic patients with multifocal regional disease. 
Systemic therapies, such as sorafenib and lenvatinib have been shown to be effective in prolonging survival rates and outcomes in patients with advanced HCC. These agents are multikinase inhibitors that block tyrosine kinases involved in angiogenesis, cancer development and growth, and tumor microenvironment regulation. They are used as first-line therapy in advanced HCC with contraindications to VEGF and immune checkpoint inhibitors. Immune checkpoint inhibitors are instead used together with bevacizumab in patients without contraindication. Alternative tyrosine kinase inhibitors, such as regorafenib, cabozantinib, and ramucirumab are used as second-line treatments.
Scientists are also researching new therapies for advanced HCC, including novel molecular-targeted therapies (such as STAT3 and CDK4 inhibitors) and immunotherapies to use as single agents or in combination. Several clinical trials are currently underway to investigate the efficacy and safety of these new therapies for advanced and metastatic HCC.
Hepatocellular carcinoma is a critical concern for clinicians and patients, given the cancer progression and severity. Validating new diagnostic biomarkers and developing new therapeutic approaches to overcome drug resistance will be paramount in improving patients’ survival and quality of life.
Human epidermal growth factor receptor 2 (HER2; ERBB2) has been shown to induce oncogenesis in several cancers, particularly breast and gastric cancers. HER2 is estimated to be overexpressed in ~20% of all breast cancers, and outcomes for these breast cancers were poor before HER2-targeted therapies. Our understanding of mechanisms by which HER2 drives tumor growth and metastasis led to one of the first targeted therapies for treating HER2+ breast cancers. Here we highlight what is known about HER2 and oncogenesis. and how this information can be applied to the development of new targeted therapies.
Gene amplification of the ERRB2 oncogene is one of the most common genetic defects detected in HER2+ tumors and typically causes overexpression of HER2 at the cell membrane. HER2 proteins more readily dimerize with other HER2 proteins to form homodimers or with other ERRB members to form heterodimers. These complexes induce oncogenic signaling cascades, including MAPK and PI3K/AKT/mTOR, which cause cellular proliferation, angiogenesis, and resistance to apoptosis. Due to the dominant role of HER2 in breast cancer, anti-HER2 antibodies were developed as one of the first targeted therapies. In 2006, clinical trial results of breast cancer patients treated with the anti-HER2 antibody trastuzumab showed significant improvements in progression-free survival and overall survival,. Unfortunately, ~20-25% of metastatic breast cancer patients develop resistance to anti-HER2 therapies. More recent studies have focused on engineering new forms of anti-HER2 antibodies or developing HER1/2 inhibitors that can be used alone or in combination with other targeted therapies.
The current standard of care for HER2+ breast cancer includes chemotherapy with adjuvant HER2-targeted therapies and endocrine therapy as indicated. Advances in targeted therapies are further improving treatment protocols. The next-generation anti-HER2 monoclonal antibody margetuximab targets the same HER2 epitope as trastuzumab and is modified in its Fc domain to improve antibody-dependent cellular cytotoxicity. Margetuximab was approved by the FDA in December 2020 for the treatment of metastatic breast cancer in patients who had received prior HER2 therapies. Two different bispecific antibodies have also been developed and are in clinical trials: ZW25 is a bispecific antibody that targets two different HER2 epitopes, and PRS-343 is a bispecific antibody that targets a HER2 epitope and the 4-1BB costimulatory immunoreceptor. Bispecific antibodies are under development for breast cancer and other cancers because they exploit the property that antibodies have two epitope binding sites and can be engineered to better target a single molecule or crosslink multiple molecules, like HER2 and immune checkpoint molecules.
Antibody-drug conjugates have also been evaluated as novel therapeutics that target HER2. Trastuzumab deruxtecan is an anti-HER2 antibody conjugated to a cytotoxic payload that is linked by a cleavable drug linker. This treatment has been recently approved by the FDA and it shows superior targeting of cytotoxic drugs to HER2+ tumor cells and shows efficacy on individuals who have been treated previously with anti-HER2 mAbs.
HER2-specific tyrosine kinase inhibitors have also been successful in treating HER2+ tumors, especially brain metastases because these drugs can cross the blood-brain barrier. Lapatinib, neratinib, pyrotinib, and tucatinib are four HER2-specific tyrosine kinase inhibitors used to treat HER2+ breast cancers. Lapatinib is an oral, irreversible small molecule HER1/HER2/HER4 TKI that was first approved in 2007 for the treatment of metastatic breast cancer. Neratinib is a similar, orally available irreversible small molecule HER1/HER2/HER4 TKI that showed better efficacy against EGFR mutants and has been approved for use as an adjuvant therapy following trastuzumab treatment. The development of resistance is also a problem for HER2-targeted TKIs, and pyrotinib is an experimental HER1/HER2/HER4 TKI under investigation as a potential new drug that is less prone to resistance. Tucatinib is a TKI that is highly selective for HER2 approved for use in combination with trastuzumab and capecitabine in HER2+ breast and colorectal cancers, including patients with metastases and who have received previous anti-HER2 treatment.
HER2+ breast cancers continue to be challenging to treat due to resistance and metastasis. Combination therapies with antibodies and targeted inhibitors have dramatically improved survival in HER2+ breast cancer patients, but individuals who relapse continue to be faced with limited treatment options. New antibody-drug conjugates, bispecific antibodies, and targeted inhibitors are under investigation and hold the promise of better, more durable treatment options for patients.
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Prostate cancer is one of the most common forms of cancer that affects the prostate gland in the male urogenital tract. Most prostate cancers are slow growing and are usually detected in individuals older than age 50. Although environmental factors contribute to the development of prostate cancer, risk is significantly associated with incidence among first-degree relatives. In recent years, several inherited and spontaneously mutated genes have been linked to prostate cancer. Here we highlight these findings and how they provide insight into the development of targeted prostate cancer therapies.
Prostate cancer tumors are typically characterized by a wide range of genomic aberrations including somatic copy number alterations (SCNAs), structural rearrangements, and point mutations. Metastatic prostate tumors may have hundreds of these aberrations throughout the genome, but recent studies of primary prostate tumors have been critical to defining mutations associated with tumor development. Most primary prostate tumors have SCNAs, typically in the form of deletions that target a small area of the genome1. Deletions are often seen in the tumor suppressor genes BRCA2, NKX3.1, PTEN, and RB12.
Structural rearrangements are another source of genomic variation observed in primary prostate tumors, for which the TMPRSS2:ERG rearrangement is most common and causes the androgen-responsive TMPRSS2 serine protease to drive expression of the ERG oncogene3. Other rearrangements have been linked to prostate cancer, including TMPRSS2 fusions with other ETS family members beyond ERG (ETV1 and ETV4)4. Some studies have suggested a link between ERG rearrangements and SCNA incidence, although it is not yet clear if rearrangements lead to destabilization of the genome and increased occurrence of SCNAs1.
Somatic mutations occur on relatively high frequency primary prostate tumors, and this has been linked to mutations DNA mismatch repair proteins, tumor suppressors and oncogenes. The tumor suppressor TP53 is consistently identified as mutated in prostate tumors5. Mutations in the tumor suppressor genes BRCA1 and BRCA2 are well known for their association with breast and ovarian cancer but have also been linked to prostate cancer, and recent studies have shown that certain BRCA2 pathogenic sequence variants are associated with an elevated risk for aggressive prostate cancer6,7. PALB2 is a protein that interacts with BRCA2, and a recent study indicated that individuals who have certain PALB2 variants are more predisposed to aggressive forms of prostate cancer8. In addition, mutations in genes associated with DNA mismatch repair (MMR), such as MSH2, MSH6, and MLH1, are associated with greater prostate cancer risk9, and individuals with Lynch syndrome, which is caused by a germline mutation in one of these MMR genes, are also at greater risk of developing an aggressive form of prostate cancer10.
One of the most important genes involved in prostate cancer progress is the gene expressing the androgen receptor (AR). Dozens of somatic mutations have been identified in the AR, and many of these mutations target the ligand binding domain11. Some prostate cancers can be treated successfully with drugs that inhibit AR signaling, such as enzalutamide, but resistance frequently occurs and is associated with worse outcomes. AR promotes prostate cancer cell survival by regulating several cellular programs. Although AR activity inhibition through androgen deprivation therapy (ADT) results in the suppression of AR-related pathways and durable clinical remission12, the disease may recur as castration-resistant prostate cancer (CRPC), typically with reactivated AR signaling. In this case, patients are treated with second-generation AR pathway inhibitors such as enzalutamide and abiraterone. Unfortunately, durable complete responses under these treatments are rare, and a substantial number of CRPC tumors progress under treatment despite loss of AR signaling. CRPC with AR-null phenotype are classified as tumors with diffuse small cell or neuroendocrine (NE) characteristics (SCNPC) or as double-negative (DNPC) phenotype that lacks both NE and AR activity13. A recently described genome-wide CRISPR-Cas9 screen was used to identify kinases that could be inhibited in the presence of enzalutamide. BRAF or downstream MAPK signaling molecules were identified as targets that could be co-inhibited with enzalutamide to improve overall therapeutic effects of these drugs14.
Genomic alterations in prostate cancer are highly variable and can impact many critical cellular processes. By understanding which genes drive disease progression, potential therapeutic targets can be identified, and disease outcomes under different treatment regimens can be better predicted.
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 Ecke TH, Schlechte HH, Schiemenz K et al. TP53 gene mutations in prostate cancer progression. Anticancer Res. 2010 May 1;30(5):1579-86.
 Patel VL, Busch EL, Friebel TM, et al. Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness. Cancer Res. 2020 Feb 1;80(3):624-638.
 Oh M, Alkhushaym N, Fallatah S, et al. The association of BRCA1 and BRCA2 mutations with prostate cancer risk, frequency, and mortality: A meta-analysis. Prostate. 2019 Jun;79(8):880-895.
 Wokołorczyk D, Kluźniak W, Stempa K, Rusak B, Huzarski T, Gronwald J, Gliniewicz K, Kashyap A, Morawska S, Dębniak T, Jakubowska A. PALB2 mutations and prostate cancer risk and survival. Br. J. Cancer. 2021 May 18:1-7.
 Ritch E, Fu SY, Herberts C, Wang G, et al. Identification of hypermutation and defective mismatch repair in ctDNA from metastatic prostate cancer. Clin. Cancer Res. 2020 Mar 1;26(5):1114-25.
 Haraldsdottir S, Hampel H, Wei L, et al. Prostate cancer incidence in males with Lynch syndrome. Genet. Med. 2014 Jul;16(7):553-7.
 Ferraldeschi R, Welti J, Luo J, Attard G, de Bono JS. Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects. Oncogene. 2015 Apr 2;34(14):1745-57.
 Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004;25(2):276–308.
 Bluemn EG, Coleman IM, Lucas JM et al. Androgen receptor pathway-independent prostate cancer is sustained through FGF signaling. Cancer Cell. 2017;32(4):474–489.
 Palit SAL, van Dorp J, Vis D, Lieftink C, Linder S, Beijersbergen R, Bergman AM, Zwart W, van der Heijden MS. A kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential therapeutic implications in BRAF-mutated prostate cancer. Sci. Rep. 2021 Jul 1;11(1):13683.
Signal transduction networks are essential to normal cell growth and function, but signaling abnormalities, such as those caused by spontaneous mutations in signaling components, are the leading causes of tumor growth. The extracellular signal-regulated kinase (ERK) signaling pathway contributes to normal cell proliferation, differentiation, and survival, but components of the ERK pathway are upregulated in many tumor types, including those associated with melanoma, lung, colon and pancreatic cancers.
The critical role of the ERK pathway in cancer has resulted in the development of drugs and therapeutics that can inhibit overactivation of ERK signaling molecules or target aberrant signaling pathways upstream of ERK. The emergence of precision medicine-driven cancer treatments has advanced the ERK pathway inhibitor field. Breakthroughs in cancer genomics has enabled researchers to analyze tumor sequences derived from patient data and identify novel targets in the ERK pathway. This type of computational analysis coupled with large scale in vitro screening is essential to narrowing down which novel inhibitors are studied further during preclinical development.
The use of patient-derived xenograft (PDX) mouse models is critical to the discovery of next-generation ERK inhibitors. PDX models involve the use of mice that are engrafted with tumor tissue derived from patient samples. These mice typically have suppressed immune systems in order to tolerate tumor grafts and can be engineered to express other components of the human immune system, such as immune checkpoint inhibitors. PDX models that use tumors with mutations in ERK signaling, such as a colorectal tumor with a V600-mutated BRAF molecule, can be used in the preclinical screening of novel ERK pathway inhibitors. Novel inhibitors can be screened simultaneously in different PDX models, and the safety and efficacy of these molecules can also be assessed in combination with other therapeutics.
We are entering an era when cancer patients will have access to precision medicine treatments informed by the genetic analysis of their tumors, and the strategic deployment of new and improved ERK pathway inhibitors in patients with specific ERK mutations will improve treatment efficacy and overall survival. PDX models are essential to the development of these new ERK pathway inhibitors and many other novel immunotherapies.
Sarcomas are a group of aggressive heterogeneous tumors for which more than 100 histological subtypes have been defined1. Sarcomas are found in a variety of solid tissues, including bone and gastrointestinal stromal cells. Current treatment options include radiotherapy, surgical resection, targeted therapies, and chemotherapy, but these treatments have had limited efficacy on intermediate to high-grade tumors. Investigations into the molecular and cellular mechanisms that drive sarcomas have helped identify potential biomarkers that can serve as potential therapeutic targets. In addition, recent studies have also focused on the tumor microenvironment (TME) within sarcomas and the roles of different immune cell subsets creating an immunosuppressive microenvironment. These observations directly inform novel immunotherapeutic approaches that are being examined in preclinical and clinical studies.
Sarcoma TME and Immune Checkpoint Blockade
In general, sarcoma TMEs are highly immunosuppressive environments, and a recent analysis of the Ewing’s sarcoma family of tumors (ESFT) showed poor overall survival correlated with tumors that had a TME with elevated expression of hypoxia-inducible factor 1-α and were enriched with immunosuppressive M2 macrophages and neutrophils2. The presence of tumor-associated macrophages has also been linked to sarcoma growth and metastasis, and elevated expression of the immune checkpoint molecule PD-L1 also correlated with metastasis and poor overall survival3,4. These observations led to clinical trials that evaluated the efficacy of immune checkpoint blockade for treating sarcomas, but treatments that targeted PD-1/PD-L1 or CTLA-4 showed limited clinical efficacy and did not meet primary endpoints for overall survival5,6.
Genomic studies of sarcomas have been critical to identifying mutations associated with tumor growth, angiogenesis, and metastasis. These findings led to clinical trials examining the efficacy of tyrosine kinase inhibitors or inhibitors that target vascular endothelial growth factor or insulin-like growth factor-1, but most of these trials failed to meet overall survival endpoints7,8. More recent genomic studies have indicated that mutations associated with different tumors occur in the same genes as some of the targeted therapies, but the mutations differ sufficiently to render these therapies ineffective9.
Cell-based immunotherapies have shown great promise in treating hematologic malignancies and are being explored for solid tumors. Chimeric antigen receptor (CAR) T cells have been of particular interest as they are patient-derived T cells engineered to express a tumor-specific receptor and thus can target tumors without being detected as foreign cells. Preclinical studies suggested that sarcoma-specific CAR T cells may be effective, but clinical trials have failed due to poor penetration and function of CAR T cells in the immunosuppressive TME10.
Recent and ongoing studies are exploring the effects of multi-CAR T cell strategies that target different tumor antigens, as well as the effects of using modified dendritic cells or natural killer cells or combining treatment modalities11.
Effective and lasting treatment options for sarcomas continue to be elusive but advances in genomic analysis and immune-based treatments are slowly improving outcomes. Like other cancers, clinical studies exploring treatment combinations are also showing promise and may provide critical breakthroughs for some of the most aggressive sarcomas.
1 Doyle LA. Sarcoma classification: an update based on the 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone. Cancer. 2014 Jun 15;120(12):1763-74.
2 Stahl D, Gentles AJ, Thiele R, Gütgemann I. Prognostic profiling of the immune cell microenvironment in Ewing’s Sarcoma Family of Tumors. Oncoimmunology. 2019 Dec 2;8(12):e1674113.
3 Xiao W, Klement JD, Lu C, Ibrahim ML, Liu K. IFNAR1 controls autocrine type I IFN regulation of PD-L1 expression in myeloid-derived suppressor cells. J. Immunol. 2018 Jul 1;201(1):264-77.
4 Zhu Z, Jin Z, Zhang M, Tang Y, Yang G, Yuan X, Yao J, Sun D. Prognostic value of programmed death-ligand 1 in sarcoma: a meta-analysis. Oncotarget. 2017 Aug 29;8(35):59570.
5 Maki RG, Jungbluth AA, Gnjatic S, Schwartz GK, D’Adamo DR, Keohan ML, Wagner MJ, Scheu K, Chiu R, Ritter E, Kachel J. A pilot study of anti-CTLA4 antibody ipilimumab in patients with synovial sarcoma. Sarcoma. 2013 Oct;2013.
6 Zuo W and Lingdi Z. Recent advances and application of PD-1 blockade in sarcoma." Oncotargets and Therapy 2019; 12:6887.
7 Ray-Coquard IL, Domont J, Tresch-Bruneel E, Bompas E, Cassier PA, Mir O, Piperno-Neumann S, Italiano A, Chevreau C, Cupissol D, Bertucci F. Paclitaxel given once per week with or without bevacizumab in patients with advanced angiosarcoma: a randomized phase II trial. J. Clin. Oncol. 2015 Sep 1;33(25):2797-802.
8 Tap WD, Demetri G, Barnette P, Desai J, Kavan P, Tozer R, Benedetto PW, Friberg G, Deng H, McCaffery I, Leitch I. Phase II study of Ganitumab, a fully human anti–type-1 insulin-like growth factor receptor antibody, in patients with metastatic ewing family tumors or desmoplastic small round cell tumors. J. Clin. Oncol. 2012 May 20;30(15):1849-56.
9 Trédan O, Wang Q, Pissaloux D, Cassier P, de la Fouchardière A, Fayette J, Desseigne F, Ray-Coquard I, de la Fouchardière C, Frappaz D, Heudel PE. Molecular screening program to select molecular-based recommended therapies for metastatic cancer patients: analysis from the ProfiLER trial. Ann. Oncol. 2019 May 1;30(5):757-65.
10 Thanindratarn P, Dean DC, Nelson SD, Hornicek FJ, Duan Z. Chimeric antigen receptor T (CAR-T) cell immunotherapy for sarcomas: From mechanisms to potential clinical applications. Cancer Treatment Reviews. 2020 Jan 1; 82:101934.
11 Patel S, Burga RA, Powell AB, Chorvinsky EA, Hoq N, McCormack SE, Van Pelt SN, Hanley PJ, Cruz CR. Beyond CAR T cells: other cell-based immunotherapeutic strategies against cancer. Front. Onc. 2019 Apr 10; 9:196.
Ovarian cancer remains one of the leading causes of mortality for women with gynecological cancers and continues to be associated with stubbornly low 5-year survival rates. Depending on the stage or type of ovarian cancer, localized treatments including surgical resection or radiation may be sufficient. Treatment of metastatic ovarian cancer may include surgery and radiation combined with chemotherapy. Hormone therapy is also typically combined with chemotherapy for targeted reduction of estrogen and/or stimulation of progesterone for the targeted treatment of ovarian stromal tumors that produce high levels of estrogen. Nonetheless, many of these treatments have limited efficacy for treating metastatic ovarian cancer.
Advances in targeted ovarian cancer treatments have been facilitated by identification of cellular replication machinery in some cancer subtypes, including defects in the breast cancer-associated protein (BRCA)1 and BRCA2 genes, which play critical roles in DNA repair and transcription regulation. Poly (ADP-ribose) polymerases (PARP) are a family of enzymes that can repair single strand DNA breaks through the base excision repair pathway. PARPs can work together with normal BRCA1/2 to repair double strand DNA breaks by the homologous recombination (HR) pathway. Preclinical studies have shown that PARP inhibitors are effective in cells with BRCA1/2 mutations because these mutations combined with PARP inhibition cause synthetic lethality due to blockade of multiple DNA repair pathways.
Olaparib was the first PARP inhibitor approved for the treatment of germline BRCA1/2-mutated metastatic ovarian cancer in 2014. This treatment was recommended for patients who had undergone three or more rounds of chemotherapy. Olaparib was later approved as a first-line maintenance therapy for germline or somatic BRCA1/2 mutations as well for the treatment of advanced ovarian cancers that have partial or complete responses to first-line platinum-based chemotherapies. Two other PARP inhibitors are also currently approved for different ovarian cancer diagnoses including rucaparib, which is approved for the treatment of germline BRCA1/2 mutations following two rounds of chemotherapy and for maintenance therapy following platinum-based therapies regardless of BRCA mutation status. Similarly, niraparib is approved to treat ovarian cancers with BRCA1/2 mutations or genomic instability and disease progression following platinum-based chemotherapies.
Like many other targeted therapies, some patients are completely unresponsive to treatment or develop resistance to PARP inhibitor monotherapy. Recent studies have described promising results associated with combined treatments, including PARP inhibitors combined with anti-angiogenic drugs like bevacizumab or immune check point inhibitors like pembrolizumab. There are currently three ongoing phase III first-line trials comparing the efficacy of combining PARP inhibitors and immune checkpoint blockade with VEGF inhibitors. Several thousand women are being enrolled in these studies with a goal of trying to determine if these combinations improve outcomes.
PARP inhibitors continue to be effective for treating hormone receptor-negative tumors but are less effective in treating hormone-receptor-positive ovarian tumors. Current trials are exploring the use of hormone inhibitors to disrupt hormone receptor signaling in ovarian tumors and render them sensitive to PARP inhibition.
PARP inhibitors have provided clinical benefits to ovarian cancer patients who previously had limited treatment options. Future studies will likely improve the efficacy of PARP inhibition as a monotherapy or in combination with other targeted therapies.
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 Ray-Coquard I, Pautier P, Pignata S, Pérol D, González-Martín A, Berger R, Fujiwara K, Vergote I, Colombo N, Mäenpää J, Selle F. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. New England Journal of Medicine. 2019 Dec 19;381(25):2416-28.
 Konstantinopoulos PA, Waggoner S, Vidal GA, Mita M, Moroney JW, Holloway R, Van Le L, Sachdev JC, Chapman-Davis E, Colon-Otero G, Penson RT, Matulonis UA, Kim YB, Moore KN, Swisher EM, Färkkilä A, D'Andrea A, Stringer-Reasor E, Wang J, Buerstatte N, Arora S, Graham JR, Bobilev D, Dezube BJ, Munster P. Single-Arm Phases 1 and 2 Trial of Niraparib in Combination with Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma. JAMA Oncol. 2019 Aug 1;5(8):1141-1149.
 Elyashiv, Osnat, Yien Ning Sophia Wong, and Jonathan A. Ledermann. "Frontline Maintenance Treatment for Ovarian Cancer." Current Oncology Reports 23.8 (2021): 1-10.m
 Matulonis UA, Wulf GM, Barry WT, Birrer M, Westin SN, Farooq S, Bell-McGuinn KM, Obermayer E, Whalen C, Spagnoletti T, Luo W. Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer. Annals of Oncology. 2017 Mar 1;28(3):512-8.
Gastrointestinal cancers are a heterogeneous group of cancers that can be caused by H. pylori bacterial or Epstein-Barr virus infection, chronic inflammation, or inherited or spontaneous genetic mutations. Advances in solid tumor immunotherapy for gastrointestinal cancers include the development of methods that improve the screening, evaluation, and development of more precise and robust treatments. Breakthroughs in basic and translational research are leading to better treatment options for gastrointestinal cancer, and CRISPR/Cas9-based (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) gene editing technology is at the forefront of these discoveries.
CRISPR/Cas9-based gene editing technology was originally identified in bacteria and archaea as an antiviral defense mechanism. As a gene editing application, CRISPR/Cas9 uses the Cas9 nuclease to cleave specific sequences in the target DNA and introduces modifications such as knock-in or knock-out mutations. The DNA sequence is targeted using a single-guide RNA (sgRNA) comprised of CRISPR RNA (crRNA) and trans-activating CRISPR RNA (tracRNA), and these RNAs can be expressed on the same plasmid as the Cas9 nuclease upon delivery into target cells. The crRNA/tracrRNA duplex can bind to the complementary sequence in the genomic DNA and recruit Cas9, which cleaves the target sequence and allows for DNA repair by either homology-directed repair or non-homologous end pairing. This repaired sequence is now a part of the genomic DNA and leaves virtually no trace of gene editing.
CRISPR/Cas9 gene editing has been used for several applications in oncology research and more recently to improve immune-oncology strategies. One of the earliest applications involves knockout screens in which a library of sgRNAs is used to transfect a pool of knockouts that can be used for gain-of-function or small molecule/drug screens. Genome-wide screens of cancer cell lines have been useful in identifying genes that are essential to cancer cell growth but can be prone to false-positive hits if the screens are not correctly designed or analyzed. Genome-wide screens have also been used to identify genes linked to resistance, and such gene hits have been identified in a melanoma library screen when treating with the inhibitor vemurafenib. Combinatorial CRISPR/Cas9 screens are now being used to target multiple genes, and this approach can be used for defining genetic or cellular pathways involved in cancer or characterizing drugs that target multiple genes.
CRISPR/Cas9 has moved beyond in vitro cell culture and can be used for human organoid models for studying oncogenesis. ARID1A is one of the most frequently mutated genes in solid tumors, including gastric tumors. ARID1A encodes a BAF complex subunit that normally targets BAF to AT-rich DNA sequences to regulate transcription. Mouse studies have suggested that ARID1A is involved in gastrointestinal cancer oncogenesis, but this was not validated in humans until a recent study that used CRISPR/Cas9-mediated depletion of ARID1A wild-type human gastric organoids. This ARID1A-knockout organoid system established a forward genetics model of gastric cancer that resembled gastric cancer phenotypically and identified BIRC5/Survivin as a key player in early tumorigenesis. This type of organoid model is not only useful for basic oncogenesis studies but can be used for small molecule inhibitor screens.
CRISPR/Cas9 screens can be used to validate mutations found in patients with gastrointestinal tumors. Activin A receptor type 2A (ACVR2A) is frequently mutated in patients with microsatellite instability-high gastric cancer, and a 2021 study used CRISPR/Cas9 to generate ACVR2A-knockout human gastric cancer cells. These cells exhibited less aggressive proliferation, migration, and invasion in vitro, and patients with ACVR2A mutations had better prognoses than patients with wild-type ACVR2A. Gastrointestinal stromal tumors (GIST) have been typically characterized by activation mutations in the receptor tyrosine kinase KIT, but a 2022 study using genome-wide CRISPR screening identified the complementary chromatin-modifying complexes MOZ and Menin-MLL as being essential to GIST. This finding highlights a trend in oncology research elucidating a role for chromatin regulation in tumorigenesis, which has the potential to be targeted therapeutically.
Beyond basic research, CRISPR/Cas9 is starting to be used in applications for clinical trials. A Phase II trial has recently launched that is using CRISPR/Cas9 to delete an intracellular checkpoint molecule called cytokine-induced SH2 (CISH) protein. Preclinical studies have shown that CRISPR/Cas9-mediated deletion of CISH enhanced antitumor responses, and the Phase II trial is using patient-derived CRISPR-modified T cells to treat individuals with metastatic gastrointestinal tumors.
CAR T-cells (Chimeric Antigen Receptor) have been an incredible progress in personalized therapy targeting cancer. However, different challenges hampered the availability, efficacy, and safety of this promising cell therapy. CRISPR-Cas9 technology can address many of these limitations. Desired genetic modification can be achieved with cellular precision engineering, leveraging CRISPR-Cas9-based gene editing. In addition, this approach can be exploited to overcome T-cell exhaustion, lack of CAR T-cell persistence, and toxicity related to cytokine release.
In particular, the implementation of CRISPR-Cas9 technology generated universal CAR T Cells resistant to PD1 Inhibition; or enhanced T cell function against bladder cancer disrupting CTLA-4. In the oncolytic therapy field, it has been demonstrated that HSV-1-derived CD40L-armed oncolytic therapy by CRISPR-Cas9-based gene editing boosted endogenous immunity in pancreatic ductal adenocarcinoma.
CRISPR/Cas9 gene editing will continue to transform basic and clinical research, immunotherapy, and cellular therapy providing effective and safe therapeutic strategies. Regulatory agencies are now developing frameworks to allow for the use of this revolutionary tool in a wide range of diseases.
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Bladder cancer is a relatively common form of cancer that is defined as either pre-invasive or invasive, and non-muscle invasive bladder cancer (NMIBC) is the most commonly diagnosed subtype. NMIBC is typically treated by surgical resection and/or intravesical delivery of chemo- or immunotherapy-based adjuvant treatment, and long-term efficacy is monitored by urine testing or cystoscopy. Muscle-invasive bladder cancer (MIBC) is relatively resistant to current treatment options and occurs more frequently in men. MIBC also has high rates of morbidity and mortality, and novel therapies or combination therapies are being developed to better treat this form of bladder cancer.
Here we highlight recent findings about invasive bladder cancer biology and how these observations are informing the development of new therapies.
Analysis of MIBC genomes has revealed a high mutation rate in tumors that approaches rates seen in melanoma and lung cancer. The mutational signature of many MIBC tumors is consistent with mutations associated with APOBEC (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like) cytidine deaminase, and many of the mutations are clonal, which suggests that the effects of APOBEC expression in bladder tissue occurs early in tumorigenesis. Non-invasive and invasive bladder tumors are also often classified as being highly heterogeneous, and tumor histology can be extremely variable and includes squamous, plasmacytoid, micropapillary, and small-cell carcinoma. This molecular and histological heterogeneity presents a challenge in subtyping tumors based on gene expression profiles and provides insight into why it can be difficult to identify targeted therapies that are effective against bladder cancers.
Several genes are commonly mutated in both NMIBC and MIBC, but mutation rates for some of these genes, including MLL2 and TP53, are higher in invasive tumors. TP53 mutations appear to be a critical factor associated with the transition to its invasive form. Mutations have also been identified in genes associated with the sister chromatid cohesion and segregation process (STAG2, ESPL1, FGFR3, and TACC3) and chromatin remodeling (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A, and CHD6).
NIMBC is one of the first forms of cancer treated with an immunotherapy approach in which the attenuated tuberculosis bacterial vaccine, Bacillus Calmette-Guérin (BCG), is delivered intravesically to the bladder and triggers an immune response that inhibits tumor growth. Recently, immune checkpoint inhibitor-based treatments have been examined as therapeutic options for different bladder cancers. Expression of the PD-L1 immune checkpoint molecule has been detected on both NIMBC and MIBC tumor cells and tumor-infiltrating mononuclear cells. Antibody-based blockade of PD-1/PD-L1 interactions restores anti-tumor responses mediated by T cells. Atezolizumab was the first PD-L1 inhibitor approved for the treatment of locally advanced/ metastatic urothelial carcinoma (LA/mUC) that has progressed or after cisplatin-based chemotherapy, and five different PD-L1/PD-1 inhibitors have been approved for this form of bladder cancer. Other checkpoint inhibitors that target different molecules have not shown significant improvements in overall survival or progression-free survival. Clinical trials currently underway are examining the efficacy of combinations of checkpoint inhibitors or the use of these inhibitors as an adjuvant therapy to surgical resection or chemotherapy. In addition, therapies that target specific mutations, such as FGFR, HER2, or chromatin-modifying genes, are also under investigation, and the FGFR inhibitor erdafitinib was recently approved for the treatment of LA/mUC.
Bladder cancer treatment outcomes continue to advance because of insights into the basic biology of bladder cancer, and a better understanding of molecular and immunological mechanisms associated with anti-tumor responses. The many preclinical and clinical studies currently underway for bladder cancer will contribute valuable information to new therapeutic options, especially for patients with refractory or invasive forms of bladder cancer.
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