Synthetic lethal strategies for the development of cancer therapeutics.

Synthetic lethality is a genetic phenomenon whereby the simultaneous presence of two different genetic alterations impairs cellular viability. Importantly, targeting synthetic lethal interactions offers potential therapeutic strategies for cancers with alterations in pathways that might otherwise be considered undruggable. High-throughput screening methods based on modern CRISPR-Cas9 technologies have emerged and become crucial for identifying novel synthetic lethal interactions with the potential for translation into biologically rational cancer therapeutic strategies as well as associated predictive biomarkers of response capable of guiding patient selection.

Scalp cooling therapy for chemotherapy-induced hair loss in patients with breast or gynecological cancers-an Asian tertiary institution experience.

Purpose: Scalp cooling therapy (SCT) improves chemotherapy-induced alopecia (CIA), but there are few published data about its efficacy in an Asian-predominant population. We report our tertiary institution experience of SCT in patients with breast or gynaecological cancers undergoing chemotherapy.

Methods: The Paxman scalp cooling system was employed for eligible women with breast or gynaecological cancers receiving anthracycline or taxane-based chemotherapy.

Unveiling Commonalities: Exploring Shared Characteristics in Clear-Cell Carcinomas of the Gynecologic Tract.

Clear-cell carcinomas (CCC) arising from the gynecologic tract (including from the ovary, endometrium, cervix, vulva, or vagina) represent rare but clinically significant entities with intriguing overlapping characteristics. Epidemiologically, CCCs exhibit a predilection for women of Asian ethnicity and are often associated with a previous or synchronous diagnosis of endometriosis. Pathologically, despite originating from different primary organs, CCCs of the gynecologic tract show similar morphologic and immunophenotypic features on traditional histopathology, such as the expression of napsin A and hepatocyte nuclear factor 1β on IHC, without the expression of Wilms tumor 1.

Molecular profiling of metastatic breast cancer and target-based therapeutic matching in an Asian tertiary phase I oncology unit.

Introduction: Molecular profiling of metastatic breast cancer (MBC) through the widespread use of next-generation sequencing (NGS) has highlighted actionable mutations and driven trials of targeted therapy matched to tumour molecular profiles, with improved outcomes reported using such an approach. Here, we review NGS results and treatment outcomes for a cohort of Asian MBC patients in the phase I unit of a tertiary centre.

Methods: Patients with MBC referred to a phase I unit underwent NGS via Ion AmpliSeq Cancer Hotspot v2 (ACH v2, 2014-2017) prior to institutional change to FoundationOne CDx (FM1; 2017-2022).

Comprehensive characterization of genomic features and clinical outcomes following targeted therapy and secondary cytoreductive surgery in OCCC: a single center experience.

Objective: Ovarian clear cell carcinoma (OCCC) is associated with chemoresistance. Limited data exists regarding the efficacy of targeted therapies such as immune checkpoint inhibitors (ICI) and bevacizumab, and the role of secondary cytoreductive surgery (SCS).

Methods: We retrospectively analyzed genomic features and treatment outcomes of 172 OCCC patients treated at our institution from January 2000 to May 2022.

Ataxia-Telangiectasia Mutated Loss-of-Function Displays Variant and Tissue-Specific Differences across Tumor Types.

Purpose: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed.

Experimental Design: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models.

Methylthioadenosine Phosphorylase Genomic Loss in Advanced Gastrointestinal Cancers.

Background: One of the most common sporadic homozygous deletions in cancers is 9p21 loss, which includes the genes methylthioadenosine phosphorylase (MTAP), CDKN2A, and CDKN2B, and has been correlated with worsened outcomes and immunotherapy resistance. MTAP-loss is a developing drug target through synthetic lethality with MAT2A and PMRT5 inhibitors. The purpose of this study is to investigate the prevalence and genomic landscape of MTAP-loss in advanced gastrointestinal (GI) tumors and investigate its role as a prognostic biomarker.

A review of strategies to overcome immune resistance in the treatment of advanced prostate cancer.

Immunotherapy has become integral in cancer therapeutics over the past two decades and is now part of standard-of-care treatment in multiple cancer types. While various biomarkers and pathway alterations such as dMMR and AR-V7 have been identified in advanced prostate cancer to predict immunotherapy responsiveness, the vast majority of prostate cancer remain intrinsically immune-resistant, as evidenced by low response rates to anti-PD(L)1 monotherapy. Since regulatory approval of the vaccine therapy sipuleucel-T in the biomarker-unselected population, there has not been much success with immunotherapy treatment in advanced prostate cancer.

Gestational choriocarcinoma.

Gestational choriocarcinoma accounts for 5% of gestational trophoblastic neoplasms. Approximately 50%, 25%, and 25% of gestational choriocarcinoma occur after molar pregnancies, term pregnancies, and other gestational events, respectively. The FIGO scoring system categorizes patients into low (score 0 to 6) and high risk (score 7 or more) choriocarcinoma.

PARP inhibitors: enhancing efficacy through rational combinations.

Poly (ADP-ribose) polymerase inhibitors (PARPi) have significantly changed the treatment landscape for tumours harbouring defects in genes involved in homologous repair (HR) such as BRCA1 and BRCA2. Despite initial responsiveness to PARPi, tumours eventually develop resistance through a variety of mechanisms. Rational combination strategies involving PARPi have been explored and are in various stages of clinical development.

Endometrial carcinosarcoma.

Endometrial carcinosarcoma is a rare and aggressive high-grade endometrial carcinoma with secondary sarcomatous trans-differentiation (conversion theory). The clinical presentation and diagnostic work-up roughly align with those of the more common endometrioid counterpart, although endometrial carcinosarcoma is more frequently diagnosed at an advanced stage. Endometrial carcinosarcoma is not a single entity but encompasses different histological subtypes, depending on the type of carcinomatous and sarcomatous elements.

Real-world outcomes from use of CDK4/6 inhibitors in the management of advanced/metastatic breast cancer in Asia.

Background: Oestrogen receptor positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer (BC) is the most frequently diagnosed BC subtype. Combinations of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with anti-oestrogen therapy have led to improved survival compared with anti-oestrogen therapy alone for advanced/metastatic BC. The evaluation of CDK4/6i in the real-world facilitates treatment planning, insights into the incidence of drug toxicities, dose modifications including dose delays (DDs) and dose reductions (DRs) and improves prognostic accuracy in subgroups, for example geriatric patients, who are under-represented in clinical trials.

Nuclear pCHK1 as a potential biomarker of increased sensitivity to ATR inhibition.

Excessive genomic instability coupled with abnormalities in DNA repair pathways induces high levels of 'replication stress' when cancer cells propagate. Rather than hampering cancer cell proliferation, novel treatment strategies are turning their attention towards targeting cell cycle checkpoint kinases (such as ATR, CHK1, WEE1, and others) along the DNA damage response and replicative stress response pathways, thereby allowing unrepaired DNA damage to be carried forward towards mitotic catastrophe and apoptosis. The selective ATR kinase inhibitor elimusertib (BAY 1895344) has demonstrated preclinical and clinical monotherapy activity; however, reliable predictive biomarkers of treatment benefit are still lacking.

Outcomes of a Phase II Study of Intraperitoneal Paclitaxel plus Systemic Capecitabine and Oxaliplatin (XELOX) for Gastric Cancer with Peritoneal Metastases.

Background: Adding intraperitoneal paclitaxel (IP-PTX) to paclitaxel/5-fluoropyrimidine has shown promising results in patients with gastric cancer peritoneal metastases (GCPM) but has not been studied with standard-of-care platinum/fluoropyrimidine combinations. Our goal to was evaluate IP-PTX with capecitabine/oxaliplatin (XELOX) in GCPM.

Methods: Forty-four patients with GCPM received IP PTX (40 mg/m, Days 1, 8), oral capecitabine (1000 mg/m twice daily, Days 1-14) and intravenous oxaliplatin (100 mg/m, Day 1) in 21-day cycles.

Targeting the DNA damage response beyond poly(ADP-ribose) polymerase inhibitors: novel agents and rational combinations.

Purpose Of Review: Poly(ADP-ribose) polymerase (PARP) inhibitors have transformed treatment paradigms in multiple cancer types defined by homologous recombination deficiency (HRD) and have become the archetypal example of synthetic lethal targeting within the DNA damage response (DDR). Despite this success, primary and acquired resistance to PARP inhibition inevitability threaten the efficacy and durability of response to these drugs. Beyond PARP inhibitors, recent advances in large-scale functional genomic screens have led to the identification of a steadily growing list of genetic dependencies across the DDR landscape.

Serial Tumor Molecular Profiling of Newly Diagnosed HER2-Negative Breast Cancers During Chemotherapy in Combination with Angiogenesis Inhibitors.

Background: Breast cancers are heterogeneous with variable clinical courses and treatment responses.

Objective: We sought to evaluate dynamic changes in the molecular landscape of HER2-negative tumors treated with chemotherapy and anti-angiogenic agents.

Patients And Methods: Newly diagnosed HER2-negative breast cancer patients received low-dose sunitinib or bevacizumab prior to four 2-weekly cycles of dose-dense doxorubicin and cyclophosphamide.

Phase Ib/II Dose Expansion Study of Lenvatinib Combined with Letrozole in Postmenopausal Women with Hormone Receptor-Positive Breast Cancer.

Purpose: RET is an estrogen response gene with preclinical studies demonstrating cross-talk between the RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multikinase inhibitor with potent activity against RET, in patients with metastatic breast cancer.

Patients And Methods: Patients with advanced ER+/HER2- breast cancer were treated with lenvatinib plus letrozole in a phase Ib/II trial.

Combined modality management of advanced cervical cancer including novel sensitizers.

The management of advanced cervical cancer has evolved with time. Combined modality treatments for cervical cancer have been shown to improve clinical outcomes for these patients. The role of surgery is reviewed in this article for specific situations such as the treatment of bulky lymph nodes and even in the metastatic setting.

Clear cell carcinoma of the endometrium.

Clear cell endometrial carcinoma represents an uncommon and poorly understood entity. Data from molecular/genomic profiling highlighted the importance of various signatures in assessing the prognosis of endometrial cancer according to four classes of risk (POLE mutated, MMRd, NSMP, and p53 abnormal). Unfortunately, data specific to clear cell histological subtype endometrial cancer are lacking.

Immunohistochemistry study of tumor vascular normalization and anti-angiogenic effects of sunitinib versus bevacizumab prior to dose-dense doxorubicin/cyclophosphamide chemotherapy in HER2-negative breast cancer.

Purpose: Tumor angiogenesis controlled predominantly by vascular endothelial growth factor and its receptor (VEGF-VEGFR) interaction plays a key role in the growth and propagation of cancer cells. However, the newly formed network of blood vessels is disorganized and leaky. Pre-treatment with anti-angiogenic agents can "normalize" the tumor vasculature allowing effective intra-tumoral delivery of standard chemotherapy.

Development of Next-Generation Poly(ADP-Ribose) Polymerase 1-Selective Inhibitors.

Poly(ADP-ribose) polymerase (PARP) inhibitors have transformed the therapeutic landscape for advanced ovarian cancer and expanded treatment options for other tumor types, including breast, pancreas, and prostate cancer. Yet, despite the success of PARP inhibitors in our current therapeutic armamentarium, not all patients benefit because of primary resistance, whereas different acquired resistance mechanisms can lead to disease progression on therapy. In addition, the toxicity profile of PARP inhibitors, primarily myelosuppression, has led to adverse events in a proportion of patients as monotherapy, and has limited the use of PARP inhibitors for certain rational combination strategies, such as chemotherapy and targeted therapy regimens.

PRL-3 dephosphorylates p38 MAPK to promote cell survival under stress.

Hypoxia within the tumor microenvironment, which leads to excessive ROS and genomic instability, is one of the hallmarks of cancer, contributing to self-renewal capability, metastasis, and radio-chemotherapy resistance. PRL-3 is an oncoprotein involved in various pro-survival signaling pathways, such as Ras/Erk, PI3K/Akt, Src/STAT, mTORC1 and JAK/STAT. However, there is little evidence connecting PRL-3-mediated apoptosis resistance to tumor microenvironmental stress.

A Tale of Two Checkpoints: ATR Inhibition and PD-(L)1 Blockade.

Innate immunity and the DNA damage response (DDR) pathway are inextricably linked. Within the DDR, ataxia telangiectasia and Rad3-related (ATR) is a key kinase responsible for sensing replication stress and facilitating DNA repair through checkpoint activation, cell cycle arrest, and promotion of fork recovery. Recent studies have shed light on the immunomodulatory role of the ATR-CHK1 pathway in the tumor microenvironment and the specific effects of ATR inhibition in stimulating an innate immune response.