Current Cancer Drug Targets - Volume 22, Issue 6, 2022

The idea of cancer immunotherapy is to stimulate the immune system to fight tumors without destroying normal cells. One of the anticancer therapy methods, among many, is based on the use of cancer vaccines that contain tumor antigens in order to induce immune responses against tumors. However, clinical trials have shown that the use of such vaccines as monotherapy is ineffective in many cases since they do not cause a strong immune response. Particular tumors are resistant to immunotherapy due to the absence or insufficient infiltration of tumors with CD8+ T cells, and hence, they are called cold or non-inflamed tumors. Cold tumors are characterized by a lack of CD8+ T cell infiltration, the presence of anti-inflammatory myeloid cells, tumor-associated M2 macrophages, and regulatory T cells. It is very important to determine the stage of the antitumor response that does not work properly in order to use the right strategy. Applying other therapeutic methods alongside cancer vaccines can be more rational for cold tumors, which do not provoke the immune system strongly. Herein, we indicate some combinational therapies that have been used or are in progress for cold tumor treatment alongside vaccines.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death, which can be attributed to the high incidence and first diagnosis at an advanced stage. Tyrosine kinase inhibitors (TKIs), a class of small-molecule targeting drugs, are primarily used for the clinical treatment of HCC after chemotherapy because they show significant clinical efficacy and low incidence of clinical adverse reactions. However, resistance to sorafenib and other TKIs, which can be used to treat advanced HCC, poses a significant challenge. Recent mechanistic studies have shown that epithelial-mesenchymal transition or transformation (EMT), ATP binding cassette (ABC) transporters, hypoxia, autophagy, and angiogenesis are involved in apoptosis, angiogenesis, HCC cell proliferation, and TKI resistance in patients with HCC. Exploring and overcoming such resistance mechanisms is essential to extend the therapeutic benefits of TKIs to patients with TKI-resistant HCC. This review aims to summarize the potential resistance mechanism proposed in recent years and methods to reverse TKI resistance in the context of HCC.

Antibody-drug conjugates offer the possibility of directing powerful cytotoxic agents to a malignant tumor while sparing normal tissue. The challenge is to select an antibody target expressed exclusively or at highly elevated levels on the surface of tumor cells and either not all or at low levels on normal cells. The current review explores 78 targets that have been explored as antibody-drug conjugate targets. Some of these targets have been abandoned, 9 or more are the targets of FDA-approved drugs, and most remain active clinical interest. Antibody-drug conjugates require potent cytotoxic drug payloads, several of these small molecules are discussed, as are the linkers between the protein component and small molecule components of the conjugates. Finally, conclusions regarding the elements for the successful antibody-drug conjugate are discussed.

Background: Metastatic triple-negative breast cancer (mTNBC) has a poor prognosis and few effective targeted therapy options. Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has been granted accelerated approval by FDA for patients with deleterious BRCA-mutated human epidermal growth factor receptor 2 (HER2)-negative advanced/metastatic breast cancer. However, there is little data demonstrating that patients with particular forms of germline and/or somatic BRCA1/2, such as large fragment variation, can benefit from PARP inhibitors. Case Presentation: In 2011, a 40-year-old woman was diagnosed with TNBC having pT2N0M0 in the right breast, and a new irregular lesser tubercle in the left breast appeared after approximately 3 years, which was also diagnosed as TNBC. In 2017, computed tomography (CT) showed TNBC metastases to the lung and brain. A next-generation sequencing (NGS) was performed with a lung metastasis sample, and results showed a homologous recombination deficiency (HRD) score of 67, a germline large deletion of exon 2 in BRCA1, a novel somatic BRCA2-STARD13 rearrangement and copy number loss of RAD51. Since September 2017, the patient was treated with olaparib. Till the report date of this case, the patient underwent regular follow-up without disease recurrence. Conclusion: To our knowledge, this is the first case describing a patient with lung- and brainmetastatic TNBC with combined germline and somatic large rearrangement and a high HRD score who achieved a long-term benefit from olaparib monotherapy. The use of NGS is promising in the treatment of TNBC in clinical practice.