Macrophages as a Therapeutic Target in Metastatic Prostate Cancer: A Way to Overcome Immunotherapy Resistance?

Prostate cancer (PC) is the most common malignancy and the fifth cause of cancer death in men. The treatment for localized or locally advanced stages offers a high probability of cure. Even though the therapeutic landscape has significantly improved over the last decade, metastatic PC (mPC) still has a poor prognosis mainly due to the development of therapy resistance. In this context, the use of immunotherapy alone or in combination with other drugs has been explored in recent years. However, T-cell directed immune checkpoint inhibitors (ICIs) have shown limited activity with inconclusive results in mPC patients, most likely due to the highly immunosuppressive PC tumor microenvironment (TME). In this scenario, targeting macrophages, a highly abundant immunosuppressive cell type in the TME, could offer a new therapeutic strategy to improve immunotherapy efficacy. In this review, we summarize the growing field of macrophage-directed immunotherapies and discuss how these could be applied in the treatment of mPC, focusing on their combination with ICIs.

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Novel immune checkpoints beyond PD-1 in advanced melanoma

memo - Magazine of European Medical Oncology ◽

10.1007/s12254-021-00699-0 ◽

2021 ◽

Author(s):

Nina Zila ◽

Christoph Hoeller ◽

Verena Paulitschke

Keyword(s):

Clinical Trials ◽

Checkpoint Inhibitors ◽

Short Review ◽

Therapy Resistance ◽

Advanced Melanoma ◽

Immune Checkpoints ◽

Malignant Diseases ◽

Foreseeable Future ◽

Cell Responses ◽

Therapeutic Landscape

SummaryIn malignant diseases, targeting of immune checkpoints successfully changed the therapeutic landscape and helped to unleash anti-tumor T cell responses, resulting in durable clinical outcomes, but only in up to 50% of patients. The success of these therapies and the need to overcome intrinsic and acquired therapy resistance stimulated research to identify new pathways and targets. Numerous clinical trials are currently evaluating novel checkpoint inhibitors or recently developed strategies like modulating the tumor microenvironment, mostly in combination with approved therapies. This short review briefly discusses promising therapeutic targets, currently still under investigation, with the chance to realize clinical application in the foreseeable future.

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PERIOPERATIVE CHEMOTHERAPY IN LOCALLY ADVANCED GASTRIC CANCER

Arquivos de Gastroenterologia ◽

10.1590/s0004-28032013000200042 ◽

2013 ◽

Vol 50 (3) ◽

pp. 236-242 ◽

Cited By ~ 5

Author(s):

Thales Paulo BATISTA ◽

Candice Amorim de Araujo Lima SANTOS ◽

Gustavo Fernandes Godoy ALMEIDA

Keyword(s):

Gastric Cancer ◽

Therapeutic Strategy ◽

Multimodal Therapy ◽

Standard Treatment ◽

Treatment Options ◽

Locally Advanced ◽

Special Focus ◽

Perioperative Chemotherapy ◽

Locally Advanced Gastric Cancer ◽

Advanced Stages

Gastric cancer is one of the most common cancers and a main cause of cancer-related death worldwide, since the majority of patients suffering of this malignancy are usually faced with a poor prognosis due to diagnosis at later stages. In order to improve treatment outcomes, the association of surgery with chemo and/or radiotherapy (multimodal therapy) has become the standard treatment for locally advanced stages. However, despite several treatment options currently available for management of these tumors, perioperative chemotherapy has been mainly accepted for the comprehensive therapeutic strategy including an appropriated D2-gastrectomy. This manuscript presents a (nonsystematic) critical review about the use of perioperative chemotherapy, with a special focus on the drugs delivery.

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Unexpected tumor response to palliative pelvic radiotherapy in mismatch repair-deficient advanced prostate cancer: a case report

Journal of Medical Case Reports ◽

10.1186/s13256-020-02578-4 ◽

2020 ◽

Vol 14 (1) ◽

Author(s):

Giovanni Aluisio ◽

Ercole Mazzeo ◽

Frank Lohr ◽

Federica Fiocchi ◽

Stefania Bettelli ◽

...

Keyword(s):

Prostate Cancer ◽

Computed Tomography ◽

Mismatch Repair ◽

Checkpoint Inhibitors ◽

Locally Advanced ◽

Computed Tomography Scan ◽

Altered Expression ◽

First Case ◽

Repair Deficiency ◽

Tomography Scan

Abstract Background Mismatch-repair-deficiency resulting in microsatellite instability (MSI) may confer increased radiosensitivity in locally advanced/metastatic tumors and thus radiotherapy (RT) potentially might have a changing role in treating this subset of patients, alone or in combination with checkpoint inhibitors. Case presentation We report a 76 year-old Italian male patient presenting with locally advanced undifferentiated prostate cancer (LAPC), infiltrating bladder and rectum. Molecular analysis revealed high-MSI with an altered expression of MSH2 and MSH6 at immunohistochemistry. Two months after 6 chemotherapy cycles with Docetaxel associated to an LHRH analogue, a computed tomography scan showed stable disease. After palliative RT (30 Gy/10 fractions) directed to the tumor mass with a 3D-conformal setup, a follow-up computed tomography scan at 8 weeks revealed an impressive response that remained stable at computed tomography after 9 months, with sustained biochemical response. To our knowledge, this is the first case of such a sustained response to low dose RT alone in high-MSI LAPC. Conclusions Routine evaluation of MSI in patients with locally problematic advanced tumors might change treatment strategy and treatment aim in this setting, from a purely palliative approach to a quasi-curative paradigm.

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(Not-so) Unexpected Tumor Response to Palliative Pelvic Radiotherapy in Mismatch Repair-Deficient Advanced Prostate Cancer

10.21203/rs.3.rs-78086/v1 ◽

2020 ◽

Author(s):

Giovanni Aluisio ◽

Ercole Mazzeo ◽

Frank Lohr ◽

Federica Fiocchi ◽

Stefania Bettelli ◽

...

Keyword(s):

Prostate Cancer ◽

Ct Scan ◽

Mismatch Repair ◽

Checkpoint Inhibitors ◽

Locally Advanced ◽

Altered Expression ◽

First Case ◽

Repair Deficiency ◽

Changing Role

Abstract Mismatch-repair-deficiency resulting in microsatellite instability (MSI) may confer increased radiosensitivity in locally advanced/metastatic tumors and thus radiotherapy (RT) potentially might have a changing role in treating this subset of patients, alone or in combination with checkpoint inhibitors. We report a 76year-old patient presenting with locally advanced undifferentiated prostate cancer (LAPC), infiltrating bladder and rectum. Molecular analysis revealed high-MSI with an altered expression of MSH2 and MSH6 at immunohistochemistry. Two months after 6 chemotherapy cycles with Docetaxel associated to an LHRH analogue, a CT scan showed stable disease. After palliative RT (30Gy/10 fractions) directed to the tumor mass with a 3D-conformal setup, a follow-up CT scan at 8 weeks revealed an impressive response, that remained stable at CT after 9 months, with sustained biochemical response. To our knowledge, this is the first case of such a sustained response to low dose RT alone in H-MSI LAPC.Routine evaluation of MSI in patients with locally problematic advanced tumors might change treatment strategy and treatment aim in this setting, from a purely palliative approach to a quasi-curative paradigm.

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Persistent, Biologically Meaningful Prostate Cancer After 1 Year of Androgen Ablation and Docetaxel Treatment

Journal of Clinical Oncology ◽

10.1200/jco.2010.33.2999 ◽

2011 ◽

Vol 29 (18) ◽

pp. 2574-2581 ◽

Cited By ~ 58

Author(s):

Vassiliki Tzelepi ◽

Eleni Efstathiou ◽

Sijin Wen ◽

Patricia Troncoso ◽

Maria Karlou ◽

...

Keyword(s):

Prostate Cancer ◽

Lymph Node ◽

Cancer Progression ◽

Intracellular Signaling ◽

Regional Lymph Node ◽

Locally Advanced ◽

Immunohistochemical Analysis ◽

Therapy Resistance ◽

Primary Site ◽

Androgen Ablation

Purpose Clinicians are increasingly willing to treat prostate cancer within the primary site in the presence of regional lymph node or even limited distant metastases. However, no formal study on the merits of this approach has been reported. We used a preoperative clinical discovery platform to prioritize pathways for assessment as therapeutic targets and to test the hypothesis that the primary site harbors potentially lethal tumors after aggressive treatment. Patients and Methods Patients with locally advanced or lymph node–metastatic prostate cancer underwent 1 year of androgen ablation and three cycles of docetaxel therapy, followed by prostatectomy. All specimens were characterized for stage by accepted criteria. Expression of select molecular markers implicated in disease progression and therapy resistance was determined immunohistochemically and compared with that in 30 archived specimens from untreated patients with high-grade prostate cancer. Marker expression was divided into three groups: intracellular signaling pathways, stromal-epithelial interaction pathways, and angiogenesis. Results Forty patients were enrolled, 30 (75%) of whom underwent prostatectomy and two (5%) who underwent cystoprostatectomy. Twenty-nine specimens contained sufficient residual tumor for inclusion in a tissue microarray. Immunohistochemical analysis showed increased epithelial and stromal expression of CYP17, SRD5A1, and Hedgehog pathway components, and modulations of the insulin-like growth factor I pathway. Conclusion A network of molecular pathways reportedly linked to prostate cancer progression is activated after 1 year of therapy; biomarker expression suggests that potentially lethal cancers persist in the primary tumor and may contribute to progression.

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Role of ZEB family members in proliferation, metastasis and chemoresistance of prostate cancer cells: Revealing signaling networks

Current Cancer Drug Targets ◽

10.2174/1568009621666210601114631 ◽

2021 ◽

Vol 21 ◽

Author(s):

Leyla soleymani ◽

Ali Zarrabi ◽

Farid Hashemi ◽

Fardin Hashemi ◽

Amirhossein Zabolian ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cancer Metastasis ◽

Family Members ◽

Therapy Resistance ◽

Migration And Invasion ◽

Cancer Proliferation ◽

E Box ◽

Advanced Stages

: Prostate cancer (PCa) is one of the leading causes of death worldwide. A variety of strategies including surgery, chemotherapy, radiotherapy and immunotherapy are applied for PCa treatment. PCa cells are responsive towards therapy at early stages, but they can obtain resistance in the advanced stage. Furthermore, their migratory ability is high in advanced stages. It seems that genetic and epigenetic factors play an important in this case. Zinc finger E-box-binding homeobox (ZEB) is a family of transcription with two key members including ZEB1 and ZEB2. ZEB family members are known due to their involvement in promoting cancer metastasis via EMT induction. Recent studies have shown their role in cancer proliferation and inducing therapy resistance. In the current review, we focus on revealing role of ZEB1 and ZEB2 in PCa. ZEB family members that are able to significantly promote proliferation and viability of cancer cells. ZEB1 and ZEB2 enhance migration and invasion of PCa cells via EMT induction. Overexpression of ZEB1 and ZEB2 is associated with poor prognosis of PCa. ZEB1 and ZEB2 upregulation occurs during PCa progression and can provide therapy resistance to cancer cells. PRMT1, Smad2, and non-coding RNAs can function as upstream mediators of the ZEB family. Besides, Bax, Bcl-2, MRP1, N-cadherin and E-cadherin can be considered as downstream targets of ZEB family in PCa.

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